Amide derivative

ABSTRACT

The present invention provides an amide derivative represented by the following general formula (1):  
                 
 
wherein R 1  represents a saturated cyclic amino group, R 2  represents alkyl, halogen or haloalkyl, R 3  represents hydrogen or halogen, Het 2 represents pyridyl or pyrimidinyl, and Het 1 represents a group of the formula [6], or a salt thereof, and a pharmaceutical composition comprising the same as an active ingredient. 
The compound of the present invention is useful as a BCR-ABL tyrosine kinase inhibitor.

TECHNICAL FIELD

The present invention relates to an amide derivative or a salt thereof,and a pharmaceutical composition comprising an amide derivative or asalt thereof as an active ingredient.

While BCR-ABL tyrosine kinase (see, for example, Non-Patent Document 1)causes aberrant growth of cells, a compound which inhibits its activityis useful for the prevention or treatment of diseases caused by theactivity of the BCR-ABL tyrosine kinase, for example, chronicmyelogenous leukemia, acute lymphoblastic leukemia and acute myelogenousleukemia (see, for example, Non-Patent Document 2).

BACKGROUND ART

bcr is gene which exists in the human twenty-second chromosome and ablis gene which exists in the human ninth chromosome, and Philadelphiachromosome is formed by translocation of the human twenty-second andninth chromosomes. It is known that a gene product of the chromosome,BCR-ABL, is protein having tyrosine kinase activity and constantlygenerates the growth signal to cause aberrant growth of cells (see, forexample, Non-Patent Document 2).

Therefore, inhibition of the BCR-ABL tyrosine kinase activity makes itpossible to suppress cell growth caused by the kinase and a compoundwhich inhibits the activity is suited for use as a therapeutic agent fordiseases such as chronic myelogenous leukemia, acute lymphoblasticleukemia and acute myelogenous leukemia. Although Glivec® (see, forexample, Patent Document 1) has already been put on the market as a drughaving the same action, other drugs having the same action mechanismhave never been put on the market and thus it has been required todevelop more excellent medicines.

It has recently been reported that recurrence is often recognized inpatients wherein remission is attained by administration of Glivec® inBCR-ABL-positive acute lymphoblastic leukemia, in addition to examplesof blastic crisis of chronic myelogenous leukemia (see, for example,Non-Patent Document 3). As a result of examination of leukemia cells ofthe patients suffering from the recurrence of disease, the appearance ofa variant such as E255K is recognized (see, for example, Non-PatentDocuments 4 to 7). Also in examples of administration of Glivec® to thepatients with BCR-ABL-positive acute lymphoblastic leukemia, theappearance of resistant cells which mainly exhibits variation of E255Kis recognized (see, for example, Non-Patent Document 8). With anincrease in use of Glivec®, resistant patients further increase and thusit is required to develop a therapy.

Patent Document 1:

-   -   Japanese Unexamined Patent No. 6-87834    -   Patent Document 2:    -   Pamphlet of International Publication WO 02/22597

Non-Patent Document 1:

-   -   Shtivelman E, et al.: Nature, 1985, 315, 550-554

Non-Patent Document 2:

-   -   Daley G Q, et al.: Science, 1990, 247, 824-830

Non-Patent Document 3:

-   -   Druker B J, et al.: N Engl J Med, 2001, 344, 1038-1042

Non-Patent Document 4:

-   -   Weisberg E, et al.: Drug Resist Updat, 2001, 4, 22-28

Non-Patent Document 5:

-   -   Gorre M E, et al.: Science, 2001, 293, 876-880

Non-Patent Document 6:

-   -   Blagosklonny M V: Leukemia, 2002, 16, 570-572

Non-Patent Document 7:

-   -   Hochhaus A, et al.: Leukemia, 2002, 16, 2190-2196

Non-Patent Document 8:

-   -   Hofmann W-K, et al.: blood, 2002, 99, 1860-1862

Non-Patent Document 9:

-   -   Deninger W N, et al.: blood, 2000, 96, 3343-3356

Non-Patent Document 10:

-   -   J. Org. Chem., 1996, 61, 1133-1135

Non-Patent Document 11:

-   -   J. Org. Chem., 2000, 65, 1144-1157

Non-Patent Document 12:

-   -   Recl. Trav. Chim. Pays-Bas., 1950, 69, 673-699

Non-Patent Document 13:

-   -   J. Med. Chem., 2000, 43, 1508-1518

Non-Patent Document 14:

-   -   J. Med. Chem., 1975, 18, 1077-1088

Non-Patent Document 15:

-   -   Bioorg. Med. Chem. Lett., 2001, 11, 2235-2239

Non-Patent Document 16:

-   -   J. Heterocyclic Chem., 2000, 37, 1457-1462

Non-Patent Document 17:

-   -   J. Med. Chem., 2000, 43(8), 1508-1518

Non-Patent Document 18:

-   -   Khim. Geterotsikl. Soedim., 1981, (7), 958-962

Non-Patent Document 19:

-   -   J. Heterocyclic Chem., 1990, 27, 579-582

Non-Patent Document 20:

-   -   Arzneim.-Forsch./Drug Res., 1989, 39(2), 1196-1201

Non-Patent Document 21:

-   -   J. Org. Chem., 1996, 61, 7240-7241

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide an amide derivativehaving an excellent BCR-ABL tyrosine kinase inhibitory activity, or asalt thereof.

The present inventors have intensively studied about various compoundsand found that the above object is achieved by the amide derivative ofthe present invention, and thus the present invention has beencompleted.

That is, the present invention is directed to an amide derivative, whichis a compound represented by the following formula [1] in any of thefollowing cases (A) and (B), or a salt thereof (hereinafter referred toas a “compound of the present invention”).

(A)

-   -   R¹ represents a saturated cyclic amino group (the saturated        cyclic amino group may be substituted by 1 to 3 same or        different members selected from the group consisting of alkyl,        alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino,        monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl and        dialkylcarbamoyl), monoalkylamino or dialkylamino.

R² represents alkyl, halogen, haloalkyl, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, acyl, amino, monoalkylamino, dialkylamino,nitro, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl or cyano.

R³ represents hydrogen, halogen or alkoxy.

Het1 represents any of groups of the following formulas [2] to [8].

Het2 represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or1,2-dihydropyridazinyl (the Het2 may be substituted by 1 to 3 same ordifferent members selected from the group consisting of alkyl, halogenand amino).

Exception is made for a compound wherein R¹ is (i) pyrrolidinyl,piperidinyl, piperazinyl or morpholinyl, all of which may be substitutedby 1 to 3 same or different members selected from the group consistingof alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino,monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl anddialkylcarbamoyl, (ii) monoalkylamino, or (iii) dialkylamino, Het1 is agroup of the formula [6], and Het2 is pyrazinyl or pyridyl which may besubstituted by alkyl.

(B)

R¹ represents 4-methylpiperazin-1-yl, 1-pyrrolidinyl, piperidino,4-ethylpiperazin-1-yl, 4-n-propylpiperazin-1-yl,cis-3,5-dimethylpiperazin-1-yl, morpholino, dimethylamino ordiethylamino.

R² represents methyl, halogen, trifluoromethyl, methoxy,methoxycarbonyl, nitro, dimethylcarbamoyl or cyano.

R³ represents hydrogen, bromo or methoxy.

Het1 represents a group of the formula [6].

Het2 represents 3-pyridyl.

The present invention is also directed to a pharmaceutical compositioncomprising the above amide derivative or salt thereof as an activeingredient and, more particularly, to a BCR-ABL tyrosine kinaseinhibitor comprising the above amide derivative or salt thereof as anactive ingredient. Specific therapeutic agent for diseases includestherapeutic agent for chronic myelogenous leukemia, therapeutic agentfor acute lymphoblastic leukemia and therapeutic agent for acutemyelogenous leukemia.

Examples of preferable ones among the above amide derivatives or saltsthereof include the following amide derivative or a salt thereof.

An amide derivative of the general formula [1] wherein R¹ is a saturatedcyclic amino group (the saturated cyclic amino group may be substitutedby 1 to 3 same or different members selected from the group consistingof alkyl and alkoxycarbonyl), monoalkylamino or dialkylamino,

-   -   R² is alky, halogen, haloalkyl, alkoxy, alkoxycarbonyl, nitro,        dialkylcarbamoyl or cyano,    -   R³ is hydrogen, halogen or alkoxy,    -   Het1 is any of groups of the formulas [2] to [8], and    -   Het2 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or        1,2-dihydropyridazinyl (the Het2 may be substituted by 1 to 3        same or different halogen), or a salt thereof.

Examples of particularly preferable ones among the above amidederivatives include amide derivatives of the following (1) to (40), orsalts thereof:

-   (1)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide-   (2)    3-iodo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (3)    3-chloro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (4)    3-fluoro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (5)    4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (6)    4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (7)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(2-pyrazinyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (8)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamide,-   (9)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamide,-   (10)    4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamide,-   (11)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(1,2-dihydropyridazin-4-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamide,-   (12)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridazinyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (13)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (14)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyridin-2-ylamino]phenyl}benzamide,-   (15)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridin-2-ylamino]phenyl}benzamide,-   (16)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyridin-6-ylamino]phenyl}benzamide,-   (17)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)pyridin-5-ylamino]phenyl}benzamide,-   (18)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)phenylamino]phenyl}benzamide,-   (19)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino]phenyl}benzamide,-   (20)    3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[5-(3-pyridyl)-1,2,4-triazin-3-ylamino]phenyl}benzamide,-   (21)    3-methyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (22)    4-(4-methylpiperazin-1-ylmethyl)-3-nitro-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (23)    3-methoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (24)    3,5-dibromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (25)    3,5-dimethoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (26)    3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (27)    3-bromo-4-(4-ethylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (28)    3-bromo-4-[4-(n-propyl)piperazin-1-ylmethyl]-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (29)    3-bromo-4-(N,N-dimethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (30)    3-bromo-4-(N,N-diethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (31)    3-bromo-4-(1-pyrrolidinylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (32)    3-bromo-4-(piperidinomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (33)    3-bromo-4-(morpholinomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (34)₃-bromo-4-(cis-3,5-dimethylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (35)    3-bromo-4-(4-methyl-hexahydro-1H-1,4-diazepin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (36)    3-bromo-4-(1-piperazinylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (37)    4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (38)    4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide,-   (39)    3-methoxycarbonyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,    and-   (40)    3-cyano-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide.

The compound of the present invention has BCR-ABL tyrosine kinaseinhibitory activity and is useful as a therapeutic agent for diseasessuch as chronic myelogenous leukemia, acute lymphoblastic leuke andacute myelogenous leukemia (see, for example, Non-Patent Document 9).

The compound of the above formula [1] in the case (B) is seemed to bedescribed in prior art documents (see, for example, Patent Document 1 or2), but is not specifically disclosed in the publication. Also thecompound of the above formula [1] in the case (A) is not described inany documents.

The present invention will now be described in detail.

Examples of the “saturated cyclic amino group” include 4- to 8-memberedsaturated ring group which has a saturated ring group having at leastone nitrogen atom as an atom composing the ring and also may have 1 to 3same or different members selected from the group consisting of nitrogenatom, oxygen atom and sulfur atom. When the atom composing the ring ofthe cyclic amino is a nitrogen atom or a sulfur atom, the nitrogen atomor sulfur atom may form an oxide. Examples thereof include pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl andhexahydro-1H-1,4-diazepinyl. These substituents may have a bonding handat any position. Specifically, it means that “pyrrolidinyl” includes allof 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl.

“Alkyl” includes straight or branched alkyl groups having 1 to 10carbons, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl,n-heptyl, isoheptyl, n-octyl, n-nonyl and n-decyl. Straight alkyl groupshaving 1 to 3 carbon atoms are particularly preferred.

The alkyl moiety of “haloalkyl”, “alkoxycarbonyl”, “hydroxyalkyl”,“monoalkylamino”, “dialkylamino”, “monoalkylcarbamoyl”,“dialkylcarbamoyl”, “alkoxy”, “alkoxyalkyl” and “hydroxyalkyl” includesthe above-mentioned alkyl.

“Halogen” includes, for example, fluorine, chlorine, bromine and iodine.

“Haloalkyl” includes monohaloalkyl, dihaloalkyl and trihaloalkyl, andthe halogen moiety of “haloalkyl” includes the above-mentioned halogen.“Haloalkyl” includes, for example, trifluoromethyl and2,2,2-trifluoroethyl.

“Acyl” includes acyl groups having 1 to 11 carbons, for example, formyl,acetyl, propionyl, butyryl, isobutyryl, benzoyl, 1-naphthoyl and2-naphthoyl.

“Pyridyl” includes, for example, 2-pyridyl, 3-pyridyl and 4-pyridyl.

“Pyrimidinyl” includes, for example, 2-pyrimidinyl, 4-pyrimidinyl and5-pyrimidinyl.

“Pyrazinyl” includes, for example, 2-pyrazinyl.

“Pyridazinyl” includes, for example, 3-pyridazinyl and 4-pyridazinyl.

“1,2-dihydropyridazinyl” includes, for example,1,2-dihydropyridazin-3-yl and 1,2-dihydropyridazin-4-yl.

The compound of the present invention can be produced from per se knowncompound or an intermediate which can be produced with ease, forexample, by the following method. In the production of the compound ofthe present invention, it is common that the raw materials are used forreaction after protecting with proper protecting groups by the per seknown methods, when the raw materials have substituents intended not tobe reacted. After the reaction, the protecting groups can be removed byper se known methods.

wherein R¹, R², R³, Het1 and Het2 are as defined above.

This reaction is a condensation reaction of a compound [9] and acompound [10] and is therefore conducted by per se known methods used inthe condensation reaction. A compound [1] can be produced by reacting acarboxylic acid as a compound [10] or a reactive derivative thereof withan amine as a compound [9]. Examples of the reactive derivative of thecompound [10] include those which are usually used in the amidecondensation formation reaction, for example, acid halide (e.g. acidchloride, acid bromide, etc.), mixed acid anhydride, imidazolide andactive amide. When using the carboxylic acid [10], a condensing agent(e.g. 1,1′-oxalyldiimidazole,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide,diethyl cyanophosphonate, diphenylphosphoryl azide,2-chloro-1-methylpyridinium iodide, etc.) is used and the reaction isconducted at −20 to 100° C. in the presence or absence of a base (e.g.organic base such as triethylamine, N,N-diisopropyl-N-ethylamine,N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine,1,8-diazabicyclo[5.4.0]undec-7-ene, etc.). The solvent is notspecifically limited as far as it is not involved in the reaction andexamples thereof include ethers such as tetrahydrofuran and diethylether; amides such as N,N-dimethylformamide and N,N-dimethylacetamide;nitrites such as acetonitrile and propionitrile; hydrocarbons such asbenzene and toluene; halogenated hydrocarbons such as chloroform anddichloromethane; and solvent mixtures thereof. In that case, additives(e.g. 1-hydroxybenzotriazole, N-hydroxysuccinimide, etc.) can also beadded. The reaction time varies depending on the kinds of the rawmaterial and the condensing agent and the reaction temperature, but ispreferably from 30 minutes to 24 hours. The amount of the compound [10]and the condensing agent is preferably 1 to 3 mol per mol of thecompound [9]. When using an acid halide as the reactive derivative ofthe compound [10], the reaction is conducted at −20 to 100° C. using apyridine solvent such as pyridine or 4-methylpyridine or the same baseand solvent as those described above. Also 4-dimethylaminopyridine canbe added as an additive. The reaction time varies depending on the kindof the acid halide and the reaction temperature, but is preferably from30 minutes to 24 hours.

The compound [9] as the raw compound wherein Het1 is a group of theformula [6] can be prepared by the same manner as described in PatentDocument 1.

The compound [9] as the raw compound wherein Het1 is a group of theformula [4], [5] or [7] can be prepared by the following manner:

wherein Het1 and Het2 are as defined above, R⁴ and R⁵ represent alkyl orhydroxy, R⁶, R⁷ and R⁸ represent alkyl, and X¹ represents halogen.Step 1

This reaction is a cross-coupling reaction using a compound [11] and anorganoboron compound [12] or an organotin compound [13] and can beconducted by per se known methods. For example, this reaction isconducted at 20 to 200° C. in a suitable solvent in the presence of apalladium catalyst. As the palladium catalyst,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium anddichlorobis(tri-o-tolylphosphine)palladium are usually used. Thereaction solvent is not specifically limited as far as it is notinvolved in the reaction and examples thereof include ethers such astetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such asmethanol and ethanol; amides such as N,N-dimethylformamide andN,N-dimethylacetamide; hydrocarbons such as benzene, toluene and xylene;organic amines such as pyridine and triethylamine; and solvent mixturesthereof. When using the compound [12], the addition of a base (e.g.sodium hydroxide, potassium carbonate, tripotassium phosphate, etc.) isessential. The reaction time varies depending on the kind of the rawmaterial and the reaction temperature, but is preferably from 1 to 48hours.

Step 2

This reaction is a reaction of reducing an aromatic nitro group of acompound [14] into an amino group and is therefore conducted by per seknown methods used in the reducing reaction. The method includes, forexample, a method of treating with zinc or tin under the acidicconditions. According to the catalytic reduction method, for example,hydrogenation can be conducted using platinum, Raney nickel,platinum-carbon (Pt—C), palladium-carbon (Pd—C) or ruthenium complex asthe catalyst. In addition, a method of using a sulfide such as sodiumdithionite and a method of reducing with ammonium formate or hydrazinein the presence of a metal catalyst are exemplified.

The compound [11] as the raw compound wherein Het1 is a group of theformula [4] can be prepared by reacting 2,4-dichloropyridine (prepared,for example, by version of the method described in Non-Patent Document12) with 2-methyl-5-nitroaniline using the method of J. P. Wolfe et al.using a palladium catalyst (see Non-Patent Documents 10 and 11). WhenHet1 is a group of the formula [0.5], for example, the compound can beprepared by reacting 1-bromo-3-iodobenzene with 2-methyl-5-nitroaniline.When Het1 is a group of the formula [7], for example, the compound canbe prepared by reacting 2,6-dichloropyrazine with2-methyl-5-nitroaniline.

The reaction solvent is not specifically limited as far as it is notinvolved in the reaction and examples thereof include ethers such astetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; hydrocarbons suchas benzene, toluene and xylene; and solvent mixtures thereof. Thereaction is conducted at 70 to 100° C. in the presence of a base.Examples of the palladium catalyst include tris(dibenzylideneacetone)dipalladium (0), palladium (II) acetate and tri(o-tolylphosphine)palladium (0). The amount of palladium is preferably from 0.5 to 4 mol %based on the halogenated aryl. As a ligand of the palladium catalyst,for example, 1,3-bis(diphenylphosphino)propane,1,1′-bis(diphenylphosphino)ferrocene and(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [(±)-BINAP] can be used.Examples of the base include sodium t-butoxide, potassium t-butoxide,cesium carbonate, potassium carbonate and sodium carbonate. The reactiontime varies depending on the kind of the raw material and the reactiontemperature, but is preferably from 1 to 36 hours.

The compound [11] wherein Het1 is a group of [4] can also be prepared byreacting 2,4-dichloropyridine with 2-methyl-5-nitroaniline at 20 to 200°C. in a suitable solvent in the presence or absence of a base. Examplesof the base include pyridine, triethylamine,N,N-diisopropyl-N-ethylamine, potassium carbonate, sodium hydrogencarbonate and potassium hydroxide. The solvent is not specificallylimited as far as it is not involved in the reaction and examplesthereof include ethers such as tetrahydrofuran, dibutyl ether and1,4-dioxane; amides such as N,N-dimethylformamide andN,N-dimethylacetamide; hydrocarbons such as benzene and toluene;alcohols such as ethylene glycol and 2-methoxyethanol; halogenatedhydrocarbons such as chloroform and dichloromethane; dimethyl sulfoxide;and solvent mixtures thereof. The reaction time varies depending on thekind of the raw material and the reaction temperature, but is preferablyfrom 1 to 24 hours.

The compound [14a] as the raw compound (compound [14] wherein Het1 is agroup of the formula [4]) can also be prepared by the following manner:

wherein R⁴, R⁵, R⁶, R⁷, R⁷, Het2 and X¹ are as defined above, and X²represents halogen.Step 1

This reaction is a cross-coupling reaction using a compound [15] and anorganoboron compound [12] or an organotin compound [13] and can beconducted by the same manner as described above.

Step 2

A compound [17] is prepared by halogenating a compound [16]. Therefore,the reaction is conducted by per se known methods. The reaction isconducted using phosphorus oxychloride, phosphorus oxybromide,phosphorus pentachoride or phosphorus pentabromide with or withoutsolvent. The reaction solvent is not specifically limited as far as itis not involved in the reaction and examples thereof include ethers suchas tetrahydrofuran, dibutyl ether and 1,4-dioxane; amides such asN,N-dimethylformamide and N,N-dimethylacetamide; halogenatedhydrocarbons such as chloroform and dichloromethane; and solventmixtures thereof. The reaction is usually conducted at room temperatureto 130° C. and the reaction time is preferably from 20 minutes to 24hours.

Step 3

A compound [14a] can be prepared by reacting the compound [17] with acompound [18] using the above method using a palladium catalyst (see,for example, Non-Patent Documents 10 and 11).

A compound [9a] (compound [9] wherein Het1 is a group of the formula[4]) can be prepared by reacting the compound [17] with a compound [19]using the above method using a palladium catalyst (see, for example,Non-Patent Documents 10 and 11) to give a compound [20] and deprotectingthe compound [20].

wherein Het2 and X² are as defined above, and R⁹ represents a protectinggroupStep 1

The raw compound [19] can be prepared by protecting 2,4-diaminotoluenewith a suitable protecting group using per se known methods. Examples ofthe protecting group include acyl derivatives such as benzoyl, acetyland formyl; and urethane type derivatives such as benzyloxycarbonyl,t-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl. A compound [20] canbe prepared by reacting the compound [17] with the compound [19] usingthe above palladium catalyst.

Step 2

In the deprotection reaction of the compound [20], an acyl typeprotecting group is removed by hydrolysis using acid or alkali, orremoved with ammonia water or hydrazine. Examples of the acid used inthe hydrolysis include inorganic acids such as hydrochloric acid andsulfuric acid, and examples of the base include inorganic bases such assodium hydroxide and potassium hydroxide. Examples of the reactionsolvent include alcohols such as methanol and ethanol; ethers such astetrahydrofuran and 1,4-dioxane; water; and solvent mixtures thereof.The reaction temperature is from 0 to 100° C. and the reaction time isusually from several minutes to 24 hours. When the protecting group is aurethane type derivative, the protecting group can be removed byhydrogenation using a palladium catalyst, or removed with hydrochloricacid, trifluoroacetic acid, trimethylsilyl iodide or boron trifluoride,although depending on the kind of the protecting group.

The raw compound [9] wherein Het1 is a group of the formula [8] can beprepared by version of the method described in Reference Example 18described hereinafter.

The compound [10] as the raw compound can be prepared by the followingmanner:

wherein R¹, R² and R³ are as defined above, R¹⁰ represents alkyl, and X³represents a leaving group such as Cl, Br, I, OTs or OMs.Step 1

A compound [23] can be prepared by condensing a compound [21] (which canbe prepared, for example, by version of the method described inNon-Patent Document 13) with an amine [22] (wherein leaving group X³represents a leaving group such as halogen, mesylate or tosylate). Thisreaction is a nucleophilic substitution reaction of an alkyl halide andamines and is conducted by per se known methods. This reaction isconducted in a suitable solvent using an excess amine or in the presenceof a base. Examples of preferable base include pyridine, triethylamine,N,N-diisopropyl-N-ethylamine, potassium carbonate and sodium hydrogencarbonate. The solvent is not specifically limited as far as it is notinvolved in the reaction and examples thereof include ethers such astetrahydrofuran and diethyl ether; amides such as N,N-dimethylformamideand N,N-dimethylacetamide; nitrites such as acetonitrile andpropionitrile; hydrocarbons such as benzene and toluene; alcohols suchas methanol and ethanol; water; and solvent mixtures thereof. Thereaction temperature is usually from 0° C. to 100° C. The reaction timevaries depending on the kind of the raw material and the reactiontemperature, but is preferably from 30 minutes to 24 hours.

Step 2

A compound [10] can be prepared by hydrolyzing a compound [23]. Thereaction is usually conducted in a suitable solvent in the presence ofan acid or a base. Examples of the acid used in the hydrolysis includeinorganic acids such as hydrochloric acid and sulfuric acid, andexamples of the base include inorganic bases such as sodium hydroxideand potassium hydroxide. Examples of the reaction solvent includealcohols such as methanol and ethanol; ethers such as tetrahydrofuranand 1,4-dioxane; water; and solvent mixtures thereof. The reactiontemperature is usually from 0 to 100° C. and the reaction time isusually from 30 minutes to 24 hours.

wherein R¹, R², R³, Het1 and Het2 are as defined above, X⁴ representsCl, Br, I or SR¹¹, and R¹¹ represents alkyl A compound [1] can beprepared by reacting a compound [24] with a compound [25]. The reactionis conducted at 20 to 200° C. in a suitable solvent in the presence orabsence of a base. Examples of the base include pyridine, triethylamine,N,N-diisopropyl-N-ethylamine, potassium carbonate, sodium hydrogencarbonate and potassium hydroxide. The solvent is not specificallylimited as far as it is not involved in the reaction and examplesthereof include ethers such as tetrahydrofuran, dibutyl ether and1,4-dioxane; amides such as N,N-dimethylformamide andN,N-dimethylacetamide; hydrocarbons such as benzene and toluene;alcohols such as ethylene glycol and 2-methoxyethanol; halogenatedhydrocarbons such as chloroform and dichloromethane; dimethyl sulfoxide;and solvent mixtures thereof. The reaction time varies depending on thekind of the raw material and the reaction temperature, but is preferablyfrom 1 to 24 hours.

The compound [24] as the raw compound can be prepared by condensing2,4-diaminotoluene with the compound [10] by version of the process 1.

The compound [25] as the raw compound can be prepared by using2,6-dibromopyridine when Het1 is a group of the formula [2],3,5-dibromopyridine when Het1 is a group of the formula [3], or2,4-dichloropyrimidine when Het1 is a group of the formula [6] inaccordance with the process 4 described hereinafter. When Het1 is agroup of the formula [4], the compound [25] can also be prepared by themethod described in the above-mentioned process 1.

wherein R¹, R², R³ and Het2 are as defined above A compound [1b](compound [1] wherein Het1 is a group of the formula [6]) can beprepared by reacting a compound [26] or its acid addition salt with acompound [27]. The reaction is conducted at 20 to 200° C. in a suitablesolvent. The solvent is not specifically limited as far as it is notinvolved in the reaction and examples thereof include alcohols such asmethanol, ethanol, 2-propanol and 2-methoxyethanol. The amount of thecompound [27] is from 1 to 2 mol, and preferably from 1 to 1.2 mol, permol of the compound [26]. The reaction time varies depending on the kindof the raw material and the reaction temperature, but is preferably from30 minutes to 30 hours. When using the acid addition salt of thecompound [26], the reaction can be conducted by adding a suitable base(e.g. potassium carbonate, sodium hydrogen carbonate, sodium hydroxide,potassium hydroxide, etc.).

The compound [26] as the raw compound can be prepared in the form of afree salt or an acid addition salt by reacting the compound [24] withcyanamide by the method described in the document (see, for example,Non-Patent Document 14).

The compound [27] as the raw compound can be prepared, for example, byversion of the method described in Patent Document 1.

wherein R¹, R²R³, R⁴, R⁵, R⁶, R⁷, R⁸, Het1 and Het2 are as definedabove, and X⁵ represents halogen

This reaction is a cross-coupling reaction using a compound [28] and anorganoboron compound [12] or an organotin compound [13] and can beconducted by per se known methods. For example, this reaction isconducted at 20 to 200° C. in a suitable solvent in the presence of apalladium catalyst. As the palladium catalyst,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium anddichlorobis(tri-o-tolylphosphine)palladium are used. The reactionsolvent is not specifically limited as far as it is not involved in thereaction and examples thereof include ethers such as tetrahydrofuran,1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol andethanol; amides such as N,N-dimethylformamide and N,N-dimethylacetamide;hydrocarbons such as benzene, toluene and xylene; organic amines such aspyridine and triethylamine; and solvent mixtures thereof. When using thecompound [12], the addition of a base (e.g. sodium hydroxide, potassiumcarbonate, tripotassium phosphate, etc.) is essential. The reaction timevaries depending on the kind of the raw material and the reactiontemperature, but is preferably from 1 to 48 hours.

The compound [28] as the raw compound can be prepared by reacting acompound [24] with 4-hydroxy-2-(methylthio)pyridine when Het1 is a groupof the formula [4], or reacting a compound [24] with4-hydroxy-2-(methylthio)pyrimidine and treating the reaction productwith phosphorus oxychloride (see, for example, Non-Patent Document 15)when Het1 is a group of the formula [6], or reacting by the methoddescribed in the document (see, for example, Non-Patent Document 16)using a compound [24] and 2,4-dichloropyrimidine when Het1 is a group ofthe formula [6].

The compound of the present invention can be used in the form of a freebase as a medicine, however, it can be also used as a pharmaceuticallyacceptable salt made by the per se known methods. These salts includesalts of mineral acids such as hydrochloric acid, hydrobromic acid,sulfuric acid and phosphoric acid, and salts of organic acids such asacetic acid, citric acid, tartaric acid, maleic acid, succinic acid,fumaric acid, p-toluene sulfonic acid, benzene sulfonic acid and methanesulfonic acid.

The hydrochloride of the amide derivative according to the presentinvention, for example, can be obtained by dissolving the amidederivative in an alcohol solution, an ethyl acetate solution or an ethersolution of the hydrogen chloride.

As shown in test examples described hereinafter, the compound of thepresent invention has high inhibitory activity of BCR-ABL tyrosinekinase as compared with a pyrimidine derivative disclosed specificallyin Patent Document 1. Therefore, the medicine of the present inventionis useful as a preventive or therapeutic agent for diseases involved inBCR-ABL tyrosine kinase, for example, chronic myelogenous leukemia,acute lymphoblastic leukemia and acute myelogenous leukemia.

When the compound of the present invention is administered as amedicine, it can be administered to mammals, including humans, either byitself or as a pharmaceutical composition in which the compound iscontained in a pharmaceutically acceptable non-toxic and inert carrierin the proportion of, for example, 0.1 to 99.5%, or preferably 0.5 to90%.

One or more auxiliary agents for formulation such as fillers or a solid,semisolid or liquid diluent are used. It is desirable to administer thepharmaceutical composition in unit dosage form. The pharmaceuticalcomposition of the present invention can be administered intravenously,orally, directly to the target tissue, topically (e.g., transdermally)or rectally. It is a matter of course that a dosage form suitable forany of the administration modes described above is employed. It isdesirable to administer orally.

It is desirable to set the dosage of the compound as a BCR-ABL tyrosinekinase inhibitor or a therapeutic agent for chronic myelogenous leukemiaby considering the condition of the patient, such as age, body weight,and the characteristics and severity of the disease and other factorssuch as the administration route; but usually for adults, an amount inthe range of 0.1 to 1000 mg/person per day, and preferably 1 to 500mg/person per day, is generally a dose of the compound of the presentinvention.

In some cases, amounts below this range are sufficient, and conversely,in other cases larger amounts are required. It can be administered bydividing the total dosage into two or three doses per day.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now described in more detail by way ofReference Examples, Examples, Test Examples and Formulation Examples ofthe compound of the present invention, to which, however, the presentinvention is not limited.

REFERENCE EXAMPLE 1 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoylChloride Dihydrochloride

Step 1

Ethyl 3-bromo-4-methylbenzoate

10.00 g of 3-bromo-4-methylbenzoic acid was suspended in 100 ml ofethanol and 2.7 ml of concentrated sulfuric acid was added, and then themixture was heated at reflux for 22 hours. After the solvent wasdistilled off under reduced pressure, the residue was mixed with icedwater, neutralized with an aqueous saturated sodium hydrogen carbonatesolution (pH8) and then extracted with ethyl acetate. The extract waswashed with water and then dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure to obtain 10.99 g ofthe objective compound as a brown oily product.

¹H-NMR(CDCl₃)δ: 1.39(3H, t), 2.45(3H, s), 4.37(2H, q), 7.29(1H, dd),7.87(1H, dd), 8.20(1H, d)

Step 2

Ethyl 3-bromo-4-(bromomethyl)benzoate

This compound was prepared by version of the method described in thedocument (J. Med. Chem., 2000, 43(8), 1508-1518). 10.00 g of ethyl3-bromo-4-methylbenzoate obtained in the step 1 was dissolved in 125 mlof carbon tetrachloride and, after adding 6.83 g of N-bromosuccinimideand 80 g of benzoyl peroxide, the solution was heated at reflux underexposure to light from an incandescent lamp (1500 W) for 8 hours. Afterremoving insolubles by filtration, the filtrate was diluted with 500 mlof dichloromethane. The solution was washed in turn with water and anaqueous saturated sodium hydrogen carbonate solution, and then driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure to obtain 13.02 g of a crude product as a brown oilyproduct.

¹H-NMR(CDCl₃)δ: 1.40(3H, t), 2.45(3H, s), 4.37(2H, q), 4.60(2H, s),7.52(1H, d), 7.96(1H, dd), 8.24(1H, d)

Step 3

Ethyl 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoate

11.40 g of ethyl 3-bromo-4-(bromomethyl)benzoate obtained in the step 2was dissolved in 114 ml of anhydrous tetrahydrofuran and, after adding5.3 g of potassium carbonate, 2.86 g of N-methylpiperazine in 10 ml oftetrahydrofuran solution was added dropwise over 10 minutes whilestirring under an argon atmosphere at room temperature. After stirringat room temperature for 4 hours, insolubles were removed by filtrationand the solvent in the filtrate was distilled off under reducedpressure. The residue was purified by silica gel column chromatographyto obtain 7.53 g of the objective compound as a brown oily product.

¹H-NMR(CDCl₃)δ: 1.39(3H, t), 2.30(3H, s), 2.48(4H, br), 2.57(4H, br),3.63(2H, s), 4.38(2H, q), 7.57(1H, d), 7.94(1H, dd), 8.20(1H, d)

Step 4

3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic Acid Dihydrochloride

2.00 g of ethyl 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoateobtained in the step 3 was dissolved in 40 ml of methanol and, afteradding 8.8 ml of an aqueous 1N sodium hydroxide solution, the mixturewas heated at reflux for one hour. After the solvent was distilled off,the residue was dissolved in 40 ml of water. The solution was washedwith 40 ml of ether and the aqueous layer was acidified (pH2) with 1Nhydrochloric acid under ice cooling. After the water was distilled off,the operation of adding 50 ml of toluene to the residue followed byazeotropic removal of water was repeated three times to obtain 2.56 g ofa crude product as a colorless crystal.

¹H-NMR (D₂O)δ: 3.04(3H, s), 3.72(8H, br), 4.66(2H, s), 7.74(1H, d),8.05(1H, d), 8.33(1H, s)

Step 5

3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl Chloride Dihydrochloride

1.50 g of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic aciddihydrochloride obtained in the step 4 was suspended in 6.3 ml ofthionyl chloride, followed by stirring with heating for 24 hours. Thereaction solution was air-cooled and the deposited crystal was collectedby filtration and then washed with diethyl ether to obtain 1.34 g of acrude product as a colorless crystal. Melting point: 229-231° C. (withdecomposition)

¹H-NMR (D₂O)δ: 3.05(3H, s), 3.83(8H, br), 4.71(2H, s), 7.76(1H, d),8.07(1H, dd), 8.37(1H, s)

REFERENCE EXAMPLE 2 3-iodo-4-(4-methylpiperazin-1-ylmethyl)benzoylChloride Dihydrochloride

In the same manner as in Reference Example 1, except that3-iodo-4-methylbenzoic acid was used in place of 3-bromo-4-methylbenzoicacid in the step 1, a pale yellow crystal was prepared. Melting point:218-220° C. (with decomposition)

¹H-NMR (D₂O)δ: 3.09(3H, s), 3.86(8H, br), 4.71(2H, s), 7.77(1H, d),8.13(1H, dd), 8.66(1H, d)

REFERENCE EXAMPLE 3 3-chloro-4-(4-methylpiperazin-1-ylmethyl)benzoylChloride Dihydrochloride

In the same manner as in Reference Example 1, except that3-chloro-4-methylbenzoic acid was used in place of3-bromo-4-methylbenzoic acid in the step 1, a colorless crystal wasprepared. Melting point: 245-247° C. (with decomposition)

¹H-NMR (D₂O)δ: 3.07(3H, s), 3.84(8H, br), 4.71(2H, s), 7.79(1H, d),8.06(1H, dd), 8.21(1H, s)

REFERENCE EXAMPLE 4 3-fluoro-4-(4-methylpiperazin-1-ylmethyl)benzoylChloride Dihydrochloride

In the same manner as in Reference Example 1, except that3-fluoro-4-methylbenzoic-acid was used in place of3-bromo-4-methylbenzoic acid in the step 1, a colorless crystal wasprepared.

Melting point: 242-244° C. (with decomposition)

¹H-NMR (D₂O)δ: 3.01(3H, s), 3.63(4H, br), 3.84(4H, br), 4.63(2H, s),7.68(1H, t), 7.89(2H, t)

REFERENCE EXAMPLE 54-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl ChlorideDihydrochloride

In the same manner as in Reference Example 1, except that4-methyl-3-trifluorobenzoic acid was used in place of3-bromo-4-methylbenzoic acid in the step 1, a pale brown crystal wasprepared.

Melting point: 214-216° C. (with decomposition)

¹H-NMR (D₂O)δ: 3.02(3H, s), 3.81(8H, br), 4.70(2H, s), 7.91(1H, d),8.32(1H, d), 8.44(1H, s)

REFERENCE EXAMPLE 64-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline

Step 1

3-(dimethylamino)-1-(5-pyrimidinyl)-2-propen-1-one

This compound was prepared by version of the method described in thedocument (Japanese Unexamined Patent Publication (Kokai) No. 6-87834).6.01 g of N,N-dimethylformamide dimethylacetal was added to 1.54 g of5-acetylpyrimidine (Khim. Geterotsikl. Soedim., 1981, (7), 958-962) andthe mixture was heated at reflux for 15 hours. After the reactionsolution was air-cooled, a small amount of diisopropyl ether was addedand the deposited crystal was collected by filtration to obtain 1.52 gof the objective compound as a reddish brown crystal. Melting point:133-135° C.

¹H-NMR(CDCl₃)δ: 2.98(3H, s), 3.22(3H, s), 5.62(1H, d), 7.89(1H, d),9.17(2H, s), 9.27(1H, s)

Step 2

1-(2-methyl-5-nitrophenyl)guanidine

To 135 g of 1-(2-methyl-5-nitrophenyl)guanidine nitrate (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834), 21 g of sodiumhydroxide in 1.0 L of a cold aqueous solution was directly added,followed by stirring at room temperature for 10 minutes. The crystal wasfiltered, sufficiently washed with water and then forced-air dried at60° C. to obtain 102 g of the objective compound as a pale yellowcrystal.

Melting point: 135-142° C.

¹H-NMR (DMSO-d₆)δ: 2.16(3H, s), 5.31(4H, br), 7.31(1H, d), 7.48(1H, d),7.59(1H, dd)

Step 3

1-methyl-4-nitro-2-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]benzene

To 1.51 g of 3-(dimethylamino)-1-(5-pyrimidinyl)-2-propen-1-one obtainedin the step 1, 1.66 g of 1-(2-methyl-5-nitrophenyl)guanidine obtained inthe step 2 was added, followed by stirring at 120° C. for 2 hours. Tothe solidified reaction solution, 2-propanol was added and the crystalwas collected by filtration and then washed in turn with 2-propanol anddiethyl ether to obtain 1.95 g of the objective compound as a pale browncrystal.

Melting point: 200-203° C.

¹H-NMR (DMSO-d₆)δ: 2.43(3H, s), 7.53(1H, d), 7.65(1H, d), 7.91 (1H dd),8.68(1H, d), 8.77(1H, d), 9.33(2H, s), 9.47(2H, s)

Step 4

4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline

This compound was prepared by version of the method described in thedocument (Japanese Unexamined Patent Publication (Kokai) No. 6-87834).1.95 g of1-methyl-4-nitro-2-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]benzeneobtained in the step 3 was suspended in 300 ml of methanol and, afteradding 0.50 g of 10% palladium-carbon, the mixture was hydrogenated at30° C. under 4 atm for 18 hours. The catalyst was removed by filtrationand the solvent in the filtrate was distilled off under reducedpressure. The residue was purified by silica gel column chromatographyto obtain 0.60 g of the objective compound as a yellow amorphous.

¹H-NMR (CDCl₃)δ: 2.25(3H, s), 3.64(2H, br), 6.43(1H, d), 6.99(1H, s),7.01(1H, d), 7.14(1H, dd), 7.52(1H, s), 8.54(1H, dd), 9.32(1H, s),9.35(2H, s)

REFERENCE EXAMPLE 74-methyl-3-[4-(2-pyrazinyl)pyrimidin-2-ylamino]aniline

Step 1

3-(dimethylamino)-1-(2-pyrazinyl)-2-propen-1-one

This compound was prepared by version of the method described in thedocument (Japanese Unexamined Patent Publication (Kokai) No. 6-87834).To 5.00 g of 2-acetylpyrazine, 5.37 g of N,N-dimethylformamide dimethylacetal was added and the mixture was heated at reflux for 19 hours. Thereaction solution was air-cooled and the deposited crystal was dissolvedin ethyl acetate and then concentrated under reduced pressure. Afteradding a small amount of diethyl ether, the deposited crystal wascollected by filtration and then washed in turn with diethyl ether anddiisopropyl ether to obtain 5.20 g of the objective compound as a browncrystal.

¹H-NMR(CDCl₃)δ: 3.01(3H, s), 3.21(3H, s), 6.36(1H, d), 7.95(1H, d),8.61(2H, m), 9.33(1H, s)

Step 2

1-methyl-4-nitro-2-[4-(2-pyrazinyl)pyrimidin-2-ylamino]benzene

This compound was prepared by version of the method described in thedocument (Japanese Unexamined Patent Publication (Kokai) No.0.6-87834.). 2.00 g of 3-(dimethylamino)-1-(2-pyrazinyl)-2-propen-1-oneobtained in the step 1 and 2.90 g of 1-(2-methyl-5-nitrophenyl)guanidinenitrate (Japanese Unexamined Patent Publication (Kokai) No. 6-87834)were suspended in 23 ml of 2-propanol and, after adding 0.50 g of sodiumhydroxide, the mixture was heated at reflux for 20 hours. After aircooling the reaction solution, the deposited crystal was collected byfiltration to obtain 3.25 g of a crude crystal. The crude crystal wasdissolved in chloroform-methanol (2:1) and insolubles were removed byfiltration, and then the filtrate was concentrated under reducedpressure to obtain 1.93 g of the objective compound as an ocherouscrystal.

Melting point: 207-210° C.

¹H-NMR (DMSO-d₆)δ: 2.44(3H, s), 7.53(1H, d), 7.74(1H, d), 7.91(1H, dd),8.71(1H, d), 8.81(3H, m), 9.34(1H, s)., 9.47(1H, s)

Step 3

4-methyl-3-[4-(2-pyrazinyl)pyrimidin-2-ylamino]aniline

This compound was prepared by version of the method described in thedocument (Japanese Unexamined Patent Publication (Kokai) No. 6-87834).1.00 g of 1-methyl-4-nitro-2-[4-(2-pyrazinyl)pyrimidin-2-ylamino]benzeneobtained in the step 2 was suspended in 50 ml of methanol and, afteradding 100 mg of 10% palladium-carbon, the mixture was hydrogenated atroom temperature under 3 atm for 14 hours and then hydrogenated under3.4 atm for 4 hours. The catalyst was removed by filtration and thesolvent in the filtrate was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain 0.49g of the objective compound as a yellow amorphous.

¹H-NMR(CDCl₃)δ: 2.27(3H, s), 3.69(2H, br), 6.43(1H, dd), 7.00(1H, s),7.02(1H, d), 7.60(1H, d), 7.70(1H, d), 8.58(1H, d), 8.67(2H, m),9.60(1H, s)

REFERENCE EXAMPLE 83-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline

Step 1

5-acetyl-2-chloropyridine

1.84 g of ground magnesium chloride was suspended in 20 ml of tolueneand 9.4 ml of triethylamine and 4.46 g of diethyl malonate were added inturn. After stirring at room temperature for 1.5 hours, 4.84 g of6-chloronicotinoyl chloride in 10 ml of a toluene suspension was addeddropwise over 20 minutes, followed by stirring at room temperature for 2hours. After neutralizing with 60 ml of 1N hydrochloric acid, theaqueous layer was separated. The aqueous layer was further extractedwith diethyl ether and the organic layers were combined, and then thesolvent was distilled off under reduced pressure. To the resulting crudecrystal, dimethyl sulfoxide-water (25 ml-1 ml) was added, followed bystirring with heating at 150 to 160° C. for 2 hours. The reactionsolution was air-cooled and water was added, and then the depositedcrystal was collected by filtration. The deposited crystal was dissolvedin ethyl acetate and the solution was washed in turn with water andaqueous saturated sodium hydrogen carbonate solution and then dried overanhydrous magnesium sulfate. The resulting crude crystal was washed withdiisopropyl ether and then collected by filtration to obtain 2.74 g ofthe objective compound as a semitranslucent crystal.

Melting point: 101-102° C.

¹H-NMR(CDCl₃)δ: 2.64(3H, d), 7.45(1H, d), 8.20(1H, dt), 8.94(1H, d)

Step 2

1-(6-chloropyridin-3-yl)-3-(dimethylamino)-2-propen-1-one

This compound was prepared by version of the method described in thedocument (Japanese Unexamined Patent Publication (Kokai) No. 6-87834).To 2.68 g of 5-acetyl-2-chloropyridine obtained in the step 1, 2.26 g ofN,N-dimethylformamide dimethyl acetal was added and the mixture washeated at reflux for 12 hours. After air cooling, the reaction solutionwas directly purified by silica gel column chromatography. The resultingcrude crystal was washed with diethyl ether and then collected byfiltration to obtain 1.87 g of the objective compound as a yellowcrystal.

Melting point: 122-123° C.

¹H-NMR(CDCl₃)δ: 2.96(3H, s), 3.19(3H, s), 5.62(1H, d), 7.37(1H, d),7.85(1H, d), 8.16(1H, dd), 8.85(1H, d)

Step 3

2-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-1-methyl-4-nitrobenzene

To 1.83 g of 1-(6-chloropyridin-3-yl)-3-(dimethylamino)-2-propen-1-oneobtained in the step 2 and 1.69 g of 1-(2-methyl-5-nitrophenyl)guanidineobtained in the step 2 of Reference Example 6, 18 ml of 2-propanol wasadded and the mixture was heated at reflux for 16 hours. After thereaction solution was air-cooled, the deposited crystal was collected byfiltration and washed with diethyl ether. The resulting crude crystalwas purified by silica gel column chromatography to obtain 0.91 g of theobjective compound as a pale yellow crystal.

Melting point: 210-212° C.

¹H-NMR (DMSO-d₆)δ: 2.42(3H, s), 7.52(1H, d), 7.59(1H, d), 7.70(1H, d),7.90(1H, dd), 8.53(1H, dd), 8.64(1H, d), 8.75(1H, d), 9.15(1H, d),9.29(1H, s)

Step 4

3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline

To 842 mg of2-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-1-methyl-4-nitrobenzeneobtained in the step 3, 6 ml of concentrated hydrochloric acid was addedand a solution of 2.78 g of tin chloride (II) dihydrate in 4 ml ofconcentrated hydrochloric acid was added while stirring with heating at55° C. The mixture was gradually heated up to 100° C. and furtherstirred with heating at 100° C. for 15 minutes. The reaction solutionwas air-cooled and water was added, and then alkalified with an aqueous10% sodium hydroxide solution. After the addition of chloroform andstirring for a while, insolubles were removed by filtration and theaqueous layer was separated. The aqueous layer was further extractedwith chloroform and the organic layers were combined and, after dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography to obtain a crude product. The crude product wascrystallized by adding diethyl ether and the crystal was collected byfiltration to obtain 680 mg of the objective compound as a pale yellowcrystal.

Melting point: 117-118° C.

¹H-NMR(CDCl₃)δ: 2.25(3H, s), 3.63(2H, br), 6.42(1H, dd), 6.95(1H, s),7.00(1H, d), 7.10(1H, d), 7.45(1H, d), 7.54(1H, s), 8.31(1H, dd),8.50(1H, d), 9.03(1H, d)

REFERENCE EXAMPLE 93-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline

Step 1

5-bromonicotinoyl Chloride

To 5.00 g of 5-bromonicotinic acid, 74 ml of thionyl chloride was addedand the mixture was heated at reflux for 6 hours. After the solvent wasdistilled off under reduced pressure, the crystal was washed withdiisopropyl ether and collected by filtration to obtain 4.09 g of theobjective compound as a colorless crystal.

Melting point: 72-74° C.

¹H-NMR(CDCl₃)δ: 8.51(1H, t), 8.96(1H, d), 9.21(1H, d)

Step 2

3-acetyl-5-bromopyridine

1.24 g of ground magnesium chloride was suspended in 13 ml of tolueneand 6.2 ml of triethylamine and 2.93 g of diethyl malonate were added inturn. After stirring at room temperature for 1.5 hours, a suspension of4.08 g of 5-bromonicotinoyl chloride obtained in the step 1 in 10 ml oftoluene was added dropwise over 15 minutes, followed by stirring at roomtemperature for 2 hours. After neutralizing with 40 ml of 1Nhydrochloric acid, the aqueous layer was separated. The aqueous layerwas extracted with diethyl ether and the organic layers were combined,and then the solvent was distilled off under reduced pressure. To theresulting oily product, dimethyl sulfoxide-water (17 ml-0.7 ml) wasadded, followed by stirring with heating at 150 to 160° C. for 2 hours.The reaction solution was air-cooled and water was added, and then thedeposited crystal was collected by filtration. The deposited crystal wasdissolved in ethyl acetate, washed in turn with water and aqueoussaturated sodium hydrogen carbonate solution and then dried overanhydrous magnesium sulfate. 0.60 g of activated carbon (KyoryokuShirasagi MOIWY433) was added and, after standing for 10 minutes,activated carbon was removed by filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to obtain 0.89 g of the objective compound asa pale yellow crystal.

Melting point: 87-89.5° C.

¹H-NMR(CDCl₃)δ: 2.65(3H, s), 8.37(1H, t), 8.86(1H, d), 9.07(1H, d)

Step 3

1-(5-bromopyridin-3-yl)-3-(dimethylamino)-2-propen-1-one

This compound was prepared by version of the method described in thedocument (Japanese Unexamined Patent Publication (Kokai) No. 6-87834).To 859 mg of 3-acetyl-5-bromopyridine obtained in the step 2, 563 mg ofN,N-dimethylformamide dimethyl acetal was added and the mixture washeated at reflux for one hour. After air cooling, the reaction solutionwas directly purified by silica gel column chromatography. The resultingcrude crystal was washed with diethyl ether and then collected byfiltration to obtain 860 mg of the objective compound as a yellowcrystal.

Melting point: 131-131.5° C.

¹H-NMR(CDCl₃)δ: 2.98(3H, s), 3.21(3H, s), 5.63(1H, d), 7.87(1H, d),8.33(1H, t), 8.73(1H, d), 8.98(1H, d)

Step 4

2-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-1-methyl-4-nitrobenzene

To 833 mg of 1-(5-bromopyridin-3-yl)-3-(dimethylamino)-2-propen-1-oneobtained in the step 3 and 634 mg of 1-(2-methyl-5-nitrophenyl)guanidineobtained in the step 2 of Reference Example 6, 7 ml of 2-propanol wasadded and the mixture was heated at reflux for 17 hours. After thereaction solution was air-dried, the deposited crystal was collected byfiltration and washed with diethyl ether to obtain 823 mg of theobjective compound as a pale yellow crystal.

Melting point: 206-208° C.

¹H-NMR (DMSO-d₆)δ: 2.43(3H, s), 7.52(1H, d), 7.66(1H, d), 7.90(1H, dd),8.66(1H, d), 8.74(1H, d), 8.80(1H, d), 8.86(1H, d), 9.31(2H, s)

Step 5

3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline

To 807 mg of2-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-1-methyl-4-nitrobenzeneobtained in the step 4, 5 ml of concentrated hydrochloric acid was addedand a solution of 2.36 g of tin chloride (II) dihydrate in 3.5 ml ofconcentrated hydrochloric acid was added while stirring with heating at55° C. The mixture was gradually heated up to 100° C. and furtherstirred with heating at 100° C. for 15 minutes. The reaction solutionwas air-cooled and water was added, and then alkalified with an aqueous10% sodium hydroxide solution. After the addition of chloroform andstirring for a while, insolubles were removed by filtration and theaqueous layer was separated. The aqueous layer was further extractedwith chloroform and the organic layers were combined and, after dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography to obtain a crude product. The crude product wascrystallized by adding diethyl ether-ethyl acetate and the crystal wascollected by filtration to obtain 528 mg of the objective compound as ayellow crystal.

Melting point: 129.5-130° C.

¹H-NMR(CDCl₃)δ: 2.26(3H, s), 3.64(2H, br), 6.44(1H, dd), 6.99(1H, s),7.01(1H, d), 7.13(1H, d), 7.59(1H, d), 8.53(2H, m), 8.78(1H, s),9.15(1H, s)

REFERENCE EXAMPLE 103-[4-(1,2-dihydropyridazin-4-yl)pyrimidin-2-ylamino]-4-methylaniline

Step 1

4-acetylpyridazine

To 3.55 g of malonic acid monoethyl ester potassium salt and 2.21 g ofmagnesium chloride, 12 ml of N,N-dimethylformamide was added and themixture was stirred with heating at 60° C. for 4 hours (reactionsolution 1). Separately, a reaction solution (reaction solution 2) wasprepared by stirring 2.07 g of 4-pyridazinecarboxylic acid (J.Heterocyclic Chem., 1990, 27, 579-582.) and 2.95 g of1,1′-carbonylbis-1H-imidazole in 12 ml of N,N-dimethylformamide at roomtemperature for 4 hours and the reaction solution was added to thereaction solution 1, followed by stirring at room temperature for 26hours. To the reaction solution, diethyl ether was added and the mixturewas neutralized with 50 ml of 1N hydrochloric acid. The aqueous layerwas separated and the aqueous layer was further extracted four timeswith diethyl ether. The organic layers were combined and, after dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure. To the resulting oily product, dimethylsulfoxide-water (5 ml-0.4 ml) was added, followed by stirring withheating at 150 to 160° C. for 2 hours. The solvent was distilled offunder reduced pressure and the residue was purified by silica gel columnchromatography. The resulting crude crystal was washed with diisopropylether and then collected by filtration to obtain 429 mg of the objectivecompound as a pale yellow crystal.

Melting point: 66.5-67.5° C.

¹H-NMR(CDCl₃)δ: 2.70(3H, s), 7.87(1H, dd), 9.49(1H, dd), 9.62(1H, t)

Step 2

3-(dimethylamino)-1-(4-pyridazinyl)-2-propen-1-one

This compound was prepared by version of the method described in thedocument (Japanese Unexamined Patent Publication (Kokai) No. 6-87834).To 410 mg of 4-acetylpyridazine obtained in the step 1, 440 mg ofN,N-dimethylformamide dimethyl acetal was added and the mixture washeated at reflux for one hour. After air-cooling, the reaction solutionwas directly purified by silica gel column chromatography. The resultingcrude crystal was washed with diethyl ether and then collected byfiltration to obtain 341 mg of the objective compound as an orangecrystal.

Melting point: 136-138° C.

¹H-NMR(CDCl₃)δ: 3.01(3H, s), 3.24(3H, s), 5.66(1H, d), 7.85(1H, dd),7.92(1H, d), 9.32(1H, dd), 9.55(1H, t)

Step 3

1-methyl-4-nitro-2-[4-(4-pyridazinyl)pyrimidin-2-ylamino]benzene

To 327 mg of 3-(dimethylamino)-1-(4-pyridazinyl)-2-propen-1-one obtainedin the step 2 and 359 mg of 1-(2-methyl-5-nitrophenyl)guanidine obtainedin the step 2 of Reference Example 6, 4 ml of 2-propanol was added andthe mixture was heated at reflux for 22 hours. The reaction solution wasair-cooled and the deposited crystal was collected by filtration, andthen washed in turn with 2-propanol and diethyl ether to obtain 437 mgof the objective compound as a pale yellow crystal.

Melting point: 0.243-245° C.

¹H-NMR (DMSO-d₆)δ: 2.43(3H, s), 7.53(1H, d), 7.73(1H, d), 7.93(1H, dd),8.29(1H, dd), 8.73(2H, m), 9.44(2H, m), 9.88(1H, s)

Step 4

3-[4-(1,2-dihydropyridazin-4-yl)pyrimidin-2-ylamino]-4-methylaniline

To 413 mg of1-methyl-4-nitro-2-[4-(4-pyridazinyl)pyrimidin-2-ylamino]benzeneobtained in the step 3, 3 ml of concentrated hydrochloric acid was addedand a solution of 1.51 g of tin chloride (II) dihydrate in 2 ml ofconcentrated hydrochloric acid was added while stirring with heating at55° C. The mixture was gradually heated up to 100° C. and furtherstirred with heating at 100° C. for 25 minutes. The reaction solutionwas air-cooled and, after adding water, the solution was alkalified withan aqueous 10% sodium hydroxide solution. After the addition ofchloroform and stirring for a while, insolubles were removed byfiltration and the aqueous layer was separated. The aqueous layer wasfurther extracted with chloroform and the organic layers were combinedand, after drying over anhydrous magnesium sulfate, the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography to obtain 38 mg of the objective compound as apale yellow amorphous.

¹H-NMR(CDCl₃)δ: 2.24(3H, s), 4.96(2H, s), 6.37(1H, dd), 6.58(1H, dd),6.73(1H, t), 6.79(1H, s), 6.80(1H, d), 6.97(1H, d), 7.41(1H, t),7.70(1H, d), 8.27(1H, d)

REFERENCE EXAMPLE 114-methyl-3-[4-(3-pyridazinyl)pyrimidin-2-ylamino]aniline

Step 1

3-(dimethylamino)-1-(3-pyridazinyl)-2-propen-1-one

This compound was prepared by version of the method described in thedocument (Japanese Unexamined Patent Publication (Kokai) No. 6-87834).To 762 mg of 3-acetylpyridazine (Arzneim.-Forsch./Drug Res., 1989,39(2), 1196-1201), 818 mg of N,N-dimethylformamide dimethyl acetal wasadded and the mixture was heated at reflux for 1.5 hours. After aircooling, the reaction solution was directly purified by silica gelcolumn chromatography. The resulting crude crystal was washed withdiisopropyl ether and then collected by filtration to obtain 945 mg ofthe objective compound as a yellowish brown crystal.

Melting point: 102-105° C.

¹H-NMR(CDCl₃)δ: 3.04(3H, s), 3.22(3H, s), 6.69(1H, d), 7.61(1H, dd),7.99(1H, d), 8.27(1H, dd), 9.24(1H, dd)

Step 2

1-methyl-4-nitro-2-[4-(3-pyridazinyl)pyrimidin-2-ylamino]benzene

800 mg of 3-(dimethylamino)-1-(3-pyridazinyl)-2-propen-1-one obtained inthe step 1 and 876 mg of 1-(2-methyl-5-nitrophenyl)guanidine obtained inthe step 2 of Reference Example 6 were stirred with heating at 120° C.for 3 hours. The solidified reaction solution was crystallized by adding2-propanol and then washed in turn with 2-propanol and diethyl ether toobtain 1.21 g of the objective compound as a dark brown crystal.

Melting point: 275-277° C.

¹H-NMR(CF₃COOD)δ: 2.45(3H, s), 7.56(1H, br), 8.18(3H, br), 8.57(1H, br),8.75(2H, br), 9.18(1H, br), 9.79(1H, br)

Step 3

4-methyl-3-[4-(3-pyridazinyl)pyrimidin-2-ylamino]aniline

754 m of1-methyl-4-nitro-2-[4-(3-pyridazinyl)pyrimidin-2-ylamino]benzeneobtained in the step 2 was suspended in 40 ml of methanol and 4.21 g ofsodium dithionite and 3.05 g of sodium hydrogen carbonate were added,and then the mixture was heated at reflux for 5 hours. After thereaction solution was air-cooled, insolubles were removed by filtrationand the solvent was distilled off under reduced pressure. To theresidue, water and chloroform were added to separate the aqueous layer,and then the aqueous layer was extracted three times with chloroform.The organic layers were combined, washed in turn with water andsaturated saline and then dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography to obtain 247 mg of theobjective compound as a yellow oily product.

¹H-NMR(CDCl₃)δ: 2.26(3H, s), 3.65(2H, br), 6.44(1H, dd), 6.95(1H, br),7.02(1H, d), 7.54(1H, d), 7.63(1H, dd), 8.02(1H, d), 8.50(1H, dd),8.62(1H, d), 9.27(1H, dd)

REFERENCE EXAMPLE 12 4-methyl-3-[4-(3-pyridyl)pyridin-2-ylamino]aniline

Step 1

2-[(4-chloro)pyridin-2-ylamino]-1-methyl-4-nitrobenzene

This compound was prepared by version of the method described in thedocument (J. Org. Chem., 1996, 61, 7240-7241.). To 2.00 g of2,4-dichloropyridine (Recl. Trav. Chim. Pays-Bas., 1950, 69, 673-699.),2.26 g of 2-methyl-5-nitroaniline, 121 mg of palladium (II) acetate, 336mg of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [(±)-BINAP] and6.16 g of cesium carbonate, 120 ml of toluene was added, and then themixture was stirred with heating at 70° C. for 23 hours under an argonatmosphere. After insolubles were removed by filtration, the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography to obtain 2.11 g of a crude product. The crudeproduct was washed with diethyl ether to obtain 1.22 g of the objectivecompound as a yellow crystal.

Melting point: 130-133° C.

¹H-NMR(CDCl₃)δ: 2.38(3H, s), 6.40(1H, br), 6.74(1H, d), 6.85(1H, dd),7.38(1H, d), 7.90(1H, dd), 8.15(1H, d), 8.57(1H, d)

Step 2

1-methyl-4-nitro-2-[4-(3-pyridyl)pyridin-2-ylamino]benzene

To 20 ml of deaerated tetrahydrofuran-water (1:1), 264 mg of2-[(4-chloro)pyridin-2-ylamino]-1-methyl-4-nitrobenzene obtained in thestep 1, 162 mg of diethyl(3-pyridyl)borane, 470 mg of potassiumcarbonate and 173 mg of tetrakis(triphenylphosphine)palladium (0) wereadded in turn and the mixture was stirred with heating at 80° C. for 44hours under an argon atmosphere. The reaction solution was diluted withethyl acetate to separate the aqueous layer, and then the aqueous layerwas further extracted three times with ethyl acetate. The organic layerswere combined, washed in turn with water and saturated saline and driedover anhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography to obtain 247 mg of a crude product. The crude productwas crystallized by adding chloroform-methanol and then collected byfiltration to obtain 143 mg of the objective compound as an orangecrystal.

Melting point: 170-173° C.

¹H-NMR(CDCl₃)δ: 2.43(3H, s), 6.49(1H, br), 6.99(1H, s), 7.07(1H, dd),7.41(2H, m), 7.87(2H, m), 8.37(1H, d), 8.68(1H, dd), 8.69(1H, s),8.86(1H, d)

Step 3

4-methyl-3-[4-(3-pyridyl)pyridin-2-ylamino]aniline

To 126 mg of 1-methyl-4-nitro-2-[4-(3-pyridyl)pyridin-2-ylamino]benzeneobtained in the step 2, 1 ml of concentrated hydrochloric acid was addedand a solution of 465 mg of tin chloride (II) dihydrate in 1 ml ofconcentrated hydrochloric acid was added while stirring with heating at60° C. The mixture was gradually heated up to 100° C. and furtherstirred with heating at 100° C. for 40 minutes. After the reactionsolution was air-cooled, water was added and the solution was alkalifiedwith an aqueous 10% sodium hydroxide solution. The solution wasextracted three times with ethyl acetate and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The resulting crude crystal was washed with a small amount ofchloroform and then collected by filtration to obtain 93 mg of theobjective compound as a pale yellow crystal.

Melting point: 183-186° C.

¹H-NMR(CDCl₃)δ: 2.19(3H, s), 3.60(2H, br), 6.37(1H, br), 6.47(1H, dd),6.82(1H, s), 6.88(1H, d), 6.91(1H, dd), 7.04(1H, d), 7.37(1H, dd),7.83(1H, dt), 8.26(1H, d), 8.64(1H, dd), 8.81(1H, d)

REFERENCE EXAMPLE 134-methyl-3-[4-(5-pyrimidinyl)pyridin-2-ylamino]aniline

Step 1

1-methyl-4-nitro-2-[4-(5-pyrimidinyl)pyridin-2-ylamino]benzene

In the same manner as in Reference Example 12 (step 2), except thatdihydroxy(5-pyrimidinyl)borane was used in place ofdiethyl(3-pyridyl)borane, the objective compound was prepared. The crudecrystal obtained by purification with silica gel column chromatographywas washed with diethyl ether.

Yellow Crystal

Melting point: 230-232° C.

¹H-NMR (DMSO-d₆)δ: 2.42(3H, s), 7.31(1H, dd), 7.47(2H, m), 7.80(1H, dd),8.33(1H, d), 8.61(1H, s), 8.94(1H, d), 9.19(2H, s), 9.30(1H, s)

Step 2

4-methyl-3-[4-(5-pyrimidinyl)pyridin-2-ylamino]aniline

163 mg of 1-methyl-4-nitro-2-[4-(5-pyrimidinyl)pyridin-2-ylamino]benzeneobtained in the step 1 was dissolved in 32 ml oftetrahydrofuran-methanol (1:1) and 98 mg of 10% palladium-carbon wasadded. Furthermore, 284 mg of ammonium formate was added and the mixturewas heated at reflux at a bath temperature of 90° C. for 40 minutes. Thecatalyst was removed by filtration and the solvent in the filtrate wasdistilled off under reduced pressure. To the residue, water and ethylacetate were added to separate the aqueous layer. The aqueous layer wasfurther extracted with ethyl acetate. The organic layers were combinedand dried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography to obtain 149 mg of the objective compound asa pale yellow crystal.

Melting point: 179-180° C.

¹H-NMR (DMSO-d₆)δ: 2.19(3H, s), 3.62(2H, br), 6.39(1H, br), 6.49(1H,dd), 6.76(1H, s), 6.83(1H, d), 6.90(1H, dd), 7.06(1H, d), 8.31(1H, d),8.90(2H, s), 9.25(1H, s)

REFERENCE EXAMPLE 14 4-methyl-3-[2-(3-pyridyl)pyridin-6-ylamino]aniline

Step 1

2-bromo-6-(3-pyridyl)pyridine

This compound was prepared by version of the method described in thedocument (Chem. Pharm. Bull., 1985, 33(11), 4755-4763.). To 40 ml oftetrahydrofuran, 1.76 g of diethyl(3-pyridyl)borane, 5.92 g of2,6-dibromopyridine, 1.99 g of tetra-n-butylammonium bromide, 692 mg oftetrakis(triphenylphosphine)palladium (0) and 1.87 g of ground potassiumhydroxide were added in turn and the mixture was heated at reflux forthree hours under an argon atmosphere. After air cooling, the reactionsolution was diluted with ethyl acetate and insolubles were removed by,filtration. The solvent in the filtrate was distilled off under reducedpressure and ethyl acetate and saturated saline were added to theresidue to separate the aqueous layer. The organic layer was dried overanhydrous magnesium sulfate and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography to obtain 1.26 g of the objective compound as a paleyellow crystal.

¹H-NMR(CDCl₃)δ: 7.34-7.51(2H, m), 7.62-7.75(2H, m), 8.34(1H, dt),8.67(1H, dd), 9.17(1H, d)

Step 2

1-methyl-4-nitro-2-[2-(3-pyridyl)pyridin-6-ylamino]benzene

This compound was prepared by version of the method described in thedocument (J. Org. Chem., 2000, 65, 1144-1157.). To 940 mg of2-bromo-6-(3-pyridyl)pyridine obtained in the step 1, 730 mg of2-methyl-5-nitroaniline, 37 mg of tris(dibenzylideneacetone)dipalladium(0), 75 mg of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl[(±)-BINAP] and 1.82 mg of cesium carbonate, 12 ml of toluene was addedand the mixture was stirred with heating at 110° C. for 24 hours underan argon atmosphere. After air cooling, the reaction solution wasdiluted with ethyl acetate and insolubles were removed by filtration.The solvent in the filtrate was distilled off under reduced pressure andthe residue was crystallized by adding diethyl ether. The resultingcrystal was collected by filtration and then washed with ethylacetate-diethyl ether to obtain 646 mg of the objective compound as ayellow crystal.

Melting point: 148-150° C.

¹H-NMR(CDCl₃)δ: 2.42(3H, s), 6.53(1H, br), 6.80(1H, d), 7.35(2H, d),7.44(1H, dd), 7.69(1H, m), 7.83(1H, dd), 8.44(1H, dt), 8.65(1H, dd),9.09(1H, d), 9.20(1H, d)

Step 3

4-methyl-3-[2-(3-pyridyl)pyridin-6-ylamino]aniline

500 mg of 1-methyl-4-nitro-2-[2-(3-pyridyl)pyridin-6-ylamino]benzeneobtained in the step 2 was dissolved in 10 ml of ethanol and 1.05 g ofzinc (powder), 430 mg of ammonium chloride and 0.46 ml of acetic acidwere added, and then the mixture was stirred with heating at 80° C. for30 minutes. The catalyst was removed by filtration and the solvent inthe filtrate was distilled off under reduced pressure. To the residue,ethyl acetate and an aqueous saturated sodium hydrogen carbonatesolution were added to separate the aqueous layer. The aqueous layer wasfurther extracted three times with ethyl acetate. The organic layerswere combined and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure to obtain 114 mg of theobjective compound as a pale yellow amorphous.

¹H-NMR(CDCl₃)δ: 2.19(3H, s), 3.40(2H, br), 6.37(1H, br), 6.45(1H, dd),6.68(1H, d), 6.91(1H, d), 7.03(1H, d), 7.16(1H, d), 7.38(1H, dd),7.56(1H, t), 8.29(1H, dt), 8.62(1H, dt), 9.19(1H, d)

REFERENCE EXAMPLE 15 4-methyl-3-[3-(3-pyridyl)pyridin-5-ylamino]aniline

Step 1

3-bromo-5-(3-pyridyl)pyridine

In the same manner as in Reference Example 14 (step 1), except that3,5-dibromopyridine was used in place of 2,6-dibromopyridine, theobjective compound was prepared.

Colorless crystal

H-NMR(CDCl₃)δ: 7.44(1H, m), 7.88(1H, m), 8.04(1H, t), 8.68-8.77(3H, m),8.84(1H, dd)

Step 2

1-methyl-4-nitro-2-[3-(3-pyridyl)pyridin-5-ylamino]benzene

This compound was prepared by version of the method described in thedocument (J. Org. Chem., 1996, 61, 7240-7241.). To 25 mg of(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [(±)-BINAP], 2 ml oftoluene was added and (±)-BINAP was dissolved by stirring with heatingat 80° C. under an argon atmosphere. The solution was once air-cooled toroom temperature and 6 mg of palladium (II) acetate was added and,stirring for one minute, 620 mg of 3-bromo-5-(3-pyridyl)pyridineobtained in the step 1, 482 mg of 2-methyl-5-nitroaniline, 1.20 g ofcesium carbonate and 2 ml (total 4 ml) of toluene were added, followedby stirring with heating at 80° C. for 18 hours and further heating at100° C. for 24 hours under an argon atmosphere. After air cooling, thereaction solution was diluted with ethyl acetate and insolubles wereremoved by filtration. The solvent in the filtrate was distilled offunder reduced pressure and the residue was purified by silica gel columnchromatography to obtain 108 mg of the objective compound as a yellowcrystal.

Melting point: 0.195-198° C.

¹H-NMR(CDCl₃)δ: 2.41(3H, s), 5.76(1H, br), 7.39(1H, br), 7.42(1H, ddd),7.54(1H, dd), 7.83(1H, dd), 7.88(1H, m), 8.09(1H, d), 8.43(1H, d),8.50(1H, d), 8.67(1H, dd), 8.83(1H, d)

Step 3

4-methyl-3-[3-(3-pyridyl)pyridin-5-ylamino]aniline

In the same manner as in Reference Example 12 (step 3), except that1-methyl-4-nitro-2-[3-(3-pyridyl)pyridin-5-ylamino]benzene obtained inthe step 2 was used in place of1-methyl-4-nitro-2-[4-(3-pyridyl)pyridin-2-ylamino]benzene, theobjective compound was prepared. The residue obtained by concentrationunder reduced pressure was not further purified. Pale brown oily product

¹H-NMR(CDCl₃)δ: 2.16(3H, s), 3.34(2H, br), 5.78(1H, br), 6.40(1H, dd),6.61(1H, d), 7.01(1H, d), 7.33-7.40(2H, m), 7.81(1H, dt), 8.28(1H, d),8.30(1H, d), 8.61(1H, dd), 8.78(1H, d)

REFERENCE EXAMPLE 16 4-methyl-3-[3-(3-pyridyl)phenylamino]aniline

Step 1

2-(3-bromophenylamino)-1-methyl-4-nitrobenzene

This compound was prepared by version of the method described in thedocument (J. Org. Chem., 2000, 65, 1144-0.1157.). To 1.00 g of1-bromo-3-iodobenzene, 591 mg of 2-methyl-5-nitroaniline, 32 mg oftris(dibenzylideneacetone)dipalladium (0), 66 mg of(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [(±)-BINAP] and 1.61 gof cesium carbonate, 14 ml of toluene was added and the mixture wasstirred with heating at 100° C. for 36 hours under an argon atmosphere.After air cooling, insolubles were removed by filtration and the solventin the filtrate was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography to obtain 256 mg of theobjective compound as an orange crystal.

Melting point: 114-116° C.

¹H-NMR(CDCl₃)δ: 2.34(3H, s), 5.52(1H, br), 6.99(1H, m), 7.14-7.21(3H,m), 7.33(1H, d), 7.77(1H, dd), 8.02(1H, d)

Step 2

1-methyl-4-nitro-2-[3-(3-pyridyl)phenylamino]benzene

In the same manner as in Reference Example 12 (step 2), except that2-(3-bromophenylamino)-1-methyl-4-nitrobenzene obtained in the step 1was used in place of2-[(4-chloro)pyridin-2-ylamino]-1-methyl-4-nitrobenzene, the objectivecompound was prepared. The crude product obtained purified by silica gelcolumn chromatography was crystallized by adding ethyl acetate.

Yellow Crystal

Melting point: 162-165° C.

¹H-NMR (DMSO-d₆)δ: 2.36(3H, s), 7.17(1H, d), 7.30(1H, d), 7.40-7.70(5H,m), 7.93-7.95(2H, m), 8.02(1H, d), 8.57(1H, d), 8.85(1H, s)

Step 3

4-methyl-3-[3-(3-pyridyl)phenylamino]aniline

In the same manner as in Reference Example 12 (step 3), except that1-methyl-4-nitro-2-[3-(3-pyridyl)phenylamino]benzene obtained in thestep 2 was used in place of1-methyl-4-nitro-2-[4-(3-pyridyl)pyridin-2-ylamino]benzene, theobjective compound was prepared. The residue obtained by concentrationunder reduced pressure was not further purified.

Pale yellow oily product

¹H-NMR(CDCl₃)δ: 2.17(3H, s), 3.50(2H, br), 5.48(1H, br), 6.33(1H, dd),6.64(1H, d), 6.97-7.15(4H, m), 7.31-7.39(2H, m), 7.85(1H, dt), 8.57(1H,dd), 8.82(1H, d)

REFERENCE EXAMPLE 17 4-methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino]aniline

Step 1

2-[(2-chloro)pyrazin-6-ylamino]-1-methyl-4-nitrobenzene

In the same manner as in Reference Example 12 (step 1), except that2,6-dichloropyrazine was used in place of 2,4-dichloropyridine, theobjective compound was prepared.

Yellow crystal

¹H-NMR(CDCl₃)δ: 2.42(3H, s), 6.44(1H, s), 7.43(1H, d), 7.97(1H, dd),8.09(2H, d), 8.58(1H, d)

Step 2

1-methyl-4-nitro-2-[2-(3-pyridyl)pyrazin-6-ylamino]benzene

To 64 ml of deaerated tetrahydrofuran-water (1:1), 790 mg of2-[(2-chloro)pyrazin-6-ylamino]-1-methyl-4-nitrobenzene obtained in thestep 1, 406 mg of dihydroxy(3-pyridyl)borane, 1.41 g of potassiumcarbonate and 520 mg of tetrakis(triphenylphosphine)palladium (0) wereadded in turn and the mixture was heated at reflux at a bath temperatureof 100° C. for 3 hours under an argon atmosphere. 32 ml oftetrahydrofuran-water (1:1) was added and the mixture was further heatedat reflux for 3 hours and then allowed to stand at room temperatureovernight. The deposited insolubles were collected by filtration andextracted and washed with methanol, and then the solvent in the filtratewas distilled off under reduced pressure. To the residue, diethyl etherwas added and, after stirring, the crystal was collected by filtrationand then washed with methanol to obtain 270 mg of the objective compoundas an amorphous.

¹H-NMR (DMSO-d₆)δ: 2.45(3H, s), 7.51(1H, d), 7.55(1H, d), 7.85(1H, dd),8.45(1H, d), 8.50(1H, s), 8.65(1H, d), 8.74(1H, s), 9.04(1H, s),9.20(1H, d), 9.29(1H, s)

Step 3

4-methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino]aniline

107 mg of 1-methyl-4-nitro-2-[2-(3-pyridyl)pyrazin-6-ylamino]benzeneobtained in the step 2 was dissolved in 10 ml of methanol (portion wasnot dissolved and suspended) and 16 mg of 10% palladium-carbon wasadded. Furthermore, 221 mg of ammonium formate was added, followed bystirring with heating at a bath temperature of 50° C. for 15 hours. Thecatalyst was removed by filtration and the solvent in the filtrate wasdistilled off under reduced pressure. To the residue, water and ethylacetate were added to separate the aqueous layer. The aqueous layer wasfurther extracted with ethyl acetate. The organic layers were combinedand dried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure to obtain 95 mg of the objectivecompound.

¹H-NMR(CDCl₃)δ: 2.22(3H, s), 6.39(1H, s), 6.48(1H, dd), 6.99(1H, d),7.06(1H, d), 7.43(1H, ddd), 8.10(1H, s), 8.28(1H, ddd), 8.43(1H, s),8.68(1H, dd), 9.23(1H, dd)

REFERENCE EXAMPLE 184-methyl-3-[5-(3-pyridyl)-1,2,4-triazin-3-ylamino]aniline

Step 1

3-methylthio-5-(3-pyridyl)-1,2,4-triazine

First, (3-pyridyl)glyoxal hydrobromide was prepared by version of themethod described in the document (Heterocycles, 1990, 31(12),2163-2172.). 5.00 g of 3-(bromoacetyl)pyridine hydrobromide (J.Heterocyclic. Chem., 1969, 6(6), 891-900.) was suspended in 30 ml ofmethanol and 3.40 g of pyridine N-oxide was added under ice-coolstirring, followed by stirring at room temperature for 26 hours afterremoving an ice bath. This compound was used for the subsequent reactionwithout being isolated. Then, 3-methylthio-5-(3-pyridyl)-1,2,4-triazinewas prepared by version of the method described in the document (J. Med.Chem., 1979, 22(6)., 671-677.). To the solution above, 4.18 g ofS-methylthiosemicarbazide hydroiodide (Heterocycles, 1979, 12(6),745-749.) and 1.51 g of sodium hydrogen carbonate were added underice-cool stirring and 6 ml of water was added and, after slowlyreturning the temperature to room temperature, the mixture was stirredat room temperature for 57 hours. The reaction solution was alkalifiedby adding a cold aqueous saturated sodium hydrogen carbonate solution,exracted twice with ethyl acetate and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography to obtain1.37 g of a crude product. The crude product was washed with warmeddiisopropyl ether to obtain 1.13 g of the objective compound as a paleyellowish green crystal.

Melting point: 98-102° C.

¹H-NMR(CDCl₃)δ: 2.75(3H, s), 7.52(1H, ddd), 8.48(1H, ddd), 8.84(1H, dd),9.37(1H, t), 9.43(1H, s)

Step 2

3-methylsulfinyl-5-(3-pyridyl)-1,2,4-triazine

3.00 g of 3-methylthio-5-(3-pyridyl)-1,2,4-triazine obtained in the step1 was dissolved in 50 ml of dichloromethane and 5.76 g of 70%m-chloroperbenzoic acid was added under ice-cool stirring. Afterstirring under ice cooling for 20 minutes, the temperature was returnedto room temperature and 1.5 g of magnesium sulfate and 10 g of NH-SilicaGel (Chromatorex NH-DM1020, manufactured by Fuji Silysia Chemical Co.,Ltd.) was added. After stirring at room temperature for 10 minutes,insolubles were removed by filtration and the solvent in the filtratewas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography to obtain 1.65 g of a crude product.The crude product was washed with 2-propanol-diethyl ether to obtain1.07 g of the objective compound as a pale brown crystal.

Melting point: 150-152° C.

¹H-NMR(CDCl₃)δ: 3.17(3H, s), 7.58(1H, dd), 8.67(1H, dd), 8.97(1H, dd),9.47(1H, d), 9.85(1H, s)

Step 3

N-(5-amino-2-methylphenyl)acetamide

3.00 g of N-(2-methyl-5-nitrophenyl)acetamide (Can. J. Chem., 1984, 62,1292-1296.) was suspended in 100 ml of ethanol and 600 mg of 10%palladium-carbon was added, and then the mixture was hydrogenated atroom temperature under 4 atm for 3 hours. The catalyst was removed byfiltration and the solvent in the filtrate was distilled off underreduced pressure to obtain 2.50 g of a crude product. The crude productwas washed with warmed diisopropyl ether to obtain 2.37 g of theobjective compound as a pale green crystal.

Melting point: 136-139° C.

¹H-NMR (D₂O)δ: 2.00(3H, s), 3.38(3H, s), 4.84(2H, br), 6.29(1H, dd),6.67(1H, d), 6.80(1H, d), 9.01(1H, br)

Step 4

4-methyl-3-[5-(3-pyridyl)-1,2,4-triazin-3-ylamino]aniline

671 mg of N-(5-amino-2-methylphenyl)acetamide obtained in the step 3 wasdissolved in 40 ml of tetrahydrofuran and 180 mg of 60% sodium hydridewas added under ice-cool stirring. After stirring under ice cooling for5 minutes, the temperature was returned to room temperature, followed bystirring for 30 minutes and 900 mg of3-methylsulfinyl-5-(3-pyridyl)-1,2,4-triazine obtained in the step 2 wasadded. After stirring at room temperature for 3.5 hours, the reactionsolution was mixed with ice water, extracted twice with didhloromethaneand dried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography to obtain 733 mg of4-methyl-3-{N-acetyl-N-[5-(3-pyridyl)-1,2,4-triazin-3-yl]amino}anilineas an intermediate. The above compound was dissolved in 10 ml ofmethanol and 2.0 ml of an aqueous 1N sodium hydroxide solution wasadded, followed by stirring at room temperature for 45 minutes. Thereaction solution was mixed with water, extracted twice with ethylacetate and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography to obtain 478 mg of the objectivecompound as a yellowish brown amorphous.

¹H-NMR(CDCl₃)δ: 2.27(3H, s), 3.5-3.9(2H, br), 6.46(1H, dd), 7.02(1H, d),7.38(1H, br), 7.44-7.51(2H, m), 8.38(1H, dt), 8.79(1H, dd), 9.19(1H, s),9.32(1H, d)

REFERENCE EXAMPLE 19 3-methyl-4-(4-methylpiperazin-1-ylmethyl)benzoylchloride dihydrochloride

Step 1

1-(4-methoxy-2-methylbenzoyl)-4-methylpiperazine

To 3.32 g of 4-methoxy-2-methylbenzoic acid, 5.75 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4.05 gof 1-hydroxybenzotriazole, 10 ml of N,N-dimethylformamide was added.Under stirring at room temperature, a solution of 2.00 g ofN-methylpiperazine in 10 ml of N,N-dimethylformamide and a solution of1.52 g of triethylamine in 10 ml of N,N-dimethylformamide were addeddropwise in turn, followed by stirring at room temperature for 15 hours.After the solvent was distilled off under reduced pressure, an aqueoussaturated sodium hydrogen carbonate solution was added to the residueand the solution was extracted twice with ethyl acetate. After dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography to obtain 4.25 g of the objective compound as a paleyellow oily product.

¹H-NMR(CDCl₃)δ: 2.30(3H, s), 2.30(2H, br), 2.31(3H, s), 2.47(2H, br),3.27(2H, br), 3.80(3H, s), 3.80(2H, br), 6.73(1H, d), 6.75(1H, s),7.09(1H, dd)

Step 2

1-(4-hydroxy-2-methylbenzoyl)-4-methylpiperazine

4.89 g of 1-(4-methoxy-2-methylbenzoyl)-4-methylpiperazine obtained inthe step 1 was dissolved in 150 ml of dichloromethane and a solution of9.87 g of boron tribromide in 100 ml of dichloromethane was addeddropwise under ice-cool stirring. After stirring under ice cooling forone hour, the temperature was returned to room temperature and themixture was further stirred for 15 hours. The reaction solution wasice-cooled and alkalified by adding 50 ml of water and 150 ml of anaqueous saturated sodium hydrogen carbonate solution, and theninsolubles were removed by filtration. The filtrate was extracted withchloroform and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography to obtain 2.20 g of theobjective compound as a pale yellow crystal.

Melting point: 167-168° C.

¹H-NMR(CDCl₃)δ: 2.18(3H, s), 2.32(3H, s), 2.32(2H, br), 2.50(2H, br),3.30(2H, br), 3.83(2H, br), 4.17(1H, br), 6.52(1H, s), 6.54(1H, d),6.94(1H, d)

Step 3

3-methyl-4-(4-methylpiperazin-1-ylmethyl)phenol

1.96 g of 1-(4-hydroxy-2-methylbenzoyl)-4-methylpiperazine obtained inthe step 2 was dissolved in 35 ml of tetrahydrofuran and 0.317 g oflithium aluminum hydride was added by several portions under ice-coolstirring. After stirring at room temperature for 4 hours, the mixturewas ice-cooled again and 0.317 g of lithium aluminum hydride was addedby several portions under ice-cool stirring, followed by stirring atroom temperature for 15 hours. The reaction solution was ice-cooled andhydrous tetrahydrofuran was added and, after decomposing lithiumaluminum hydride, insolubles were removed by filtration. The solvent inthe filtrate was distilled off and the residue was crystallized byadding acetone to obtain 1.10 g of the objective compound as a colorlesscrystal.

Melting point: 174-176° C.

¹H-NMR(CDCl₃)δ: 2.28(3H, s), 2.29(3H, s), 2.51(8H, br), 3.39(2H, s),6.50(1H, dd), 6.54(1H, d), 7.03(1H, d)

Step 4

3-methyl-4-(4-methylpiperazin-1-ylmethyl)phenyltrifluoromethanesulfonate

660 mg of 3-methyl-4-(4-methylpiperazin-1-ylmethyl)phenol obtained inthe step 3 was dissolved in 6.6 ml of pyridine and 1.86 g of anhydroustrifluoromethanesulfonic acid was added under ice-cool stirring,followed by stirring at room temperature for 12 hours. The reactionsolution was mixed with ice water, extracted three times with ethylacetate and then washed with water. After drying over anhydrousmagnesium sulfate, the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography to obtain535 mg of the objective compound as a pale yellow oily product.

¹H-NMR(CDCl₃)δ: 2.31(3H, s), 2.38(3H, s), 2.47(8H, br), 3.45(2H, s),7.04(1H, d), 7.06(1H, s), 7.35(1H, d)

Step 5

Methyl 3-methyl-4-(4-methylpiperazin-1-ylmethyl)benzoate

705 mg of 3-methyl-4-(4-methylpiperazin-1-ylmethyl)phenyltrifluoromethanesulfonate obtained in the step 4 was dissolved insolvent mixture of 8.40 ml of dimethyl sulfoxide, 4.96 ml of methanol,2.68 ml of 1,2-dichloroethane and 0.76 ml of triethylamine, and then62.8 mg of 1,3-bis(diphenylphosphino)propane and 34.2 mg of palladium(II) acetate were added. Under stirring at room temperature, a carbonmonoxide gas was bubbled into the reaction solution for 5 minutes andthe solution was further heated at reflux for one hour while bubblingthe carbon monoxide gas. After air cooling, water and ethyl acetate wereadded to the reaction solution and insolubles were removed byfiltration, and then the filtrate was extracted with ethyl acetate. Theextract was washed with water and dried over anhydrous magnesium sulfateand the solvent was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography to obtain 392 mg of theobjective compound as a pale yellow oily product.

¹H-NMR(CDCl₃)δ: 2.29(3H, s), 2.39(3H, s), 2.46(8H, br), 3.49(2H, s),3.90(3H, s), 7.36(1H, d), 7.81(1H, d), 7.83(1H, s)

Step 6

3-methyl-4-(4-methylpiperazin-1-ylmethyl)benzoic Acid Dihydrochloride

In the same manner as in Reference Example 1 (step 4), except thatmethyl 3-methyl-4-(4-methylpiperazin-1-ylmethyl)benzoate obtained in thestep 5 was used in place of ethyl3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoate, the objective compoundwas prepared.

Colorless crystal

Step 7

3-methyl-4-(4-methylpiperazin-1-ylmethyl)benzoyl ChlorideDihydrochloride

In the same manner as in Reference Example 1 (step 5), except that3-methyl-4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochlorideobtained in the step 6 was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochloride,the objective compound was prepared.

Colorless crystal

REFERENCE EXAMPLE 20 4-(4-methylpiperazin-1-ylmethyl)-3-nitrobenzoylChloride Dihydrochloride

Step 1

Ethyl 4-(bromomethyl)-3-nitrobenzoate

In the same manner as in Reference Example 1 (step 1), except that4-(bromomethyl)-3-nitrobenzoic acid was used in place of3-bromo-4-methylbenzoic acid, the objective compound was prepared.

Yellow oily product

¹H-NMR(CDCl₃)δ: 1.43(3H, t), 4.48(2H, q), 4.85(2H, s), 7.67(1H, d),8.26(1H, dd), 8.67(1H, d)

Step 2

Ethyl 4-(4-methylpiperazin-1-ylmethyl)-3-nitrobenzoate

In the same manner as in Reference Example 1 (step 3), except that ethyl4-(bromomethyl)-3-nitrobenzoate obtained in the step 1 was used in placeof ethyl 3-bromo-4-(bromomethyl)benzoate, the objective compound wasprepared.

Yellow Crystal

Melting point: 92-94° C.

¹H-NMR(CDCl₃)δ: 1.42(3H, t), 2.28(3H, s), 2.33-2.54(8H, br), 3.83(2H,s), 4.42(2H, q), 7.71(1H, d), 8.19(1H, dd), 8.45(1H, d)

Step 3

4-(4-methylpiperazin-1-ylmethyl)-3-nitrobenzoic Acid Dihydrochloride

In the same manner as in Reference Example 1 (step 4), except that ethyl4-(4-methylpiperazin-1-ylmethyl)-3-nitrobenzoate obtained in the step 2was used in place of ethyl3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoate, the objective compoundwas prepared.

Pale Brown Crystal

Melting point: 180° C. (with decomposition)

¹H-NMR (D₂O)δ: 2.88(3H, s), 3.30-3.90(8H, br), 4.58(2H, s), 7.72(1H, d),8.24(1H, dd), 8.66(1H, d)

Step 4

4-(4-methylpiperazin-1-ylmethyl)-3-nitrobenzoyl Chloride Dihydrochloride

In the same manner as in Reference Example 1 (step 5), except that4-(4-methylpiperazin-1-ylmethyl)-3-nitrobenzoic acid dihydrochlorideobtained in the step 3 was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochloride,the objective compound was prepared.

Pale Brown Crystal

Melting point: 190° C. (with decomposition)

¹H-NMR (D₂O)δ: 2.99(3H, s), 3.25-4.00(8H, br), 4.66(2H, s), 7.75(1H, d),8.28(1H, d), 8.72(1H, br)

REFERENCE EXAMPLE 21 3-methoxy-4-(4-methylpiperazin-1-ylmethyl)benzoylChloride Dihydrochloride

In the same manner as in Reference Example 1 (steps 2 to 5), except thatmethyl 3-methoxy-4-methylbenzoate was used in place of ethyl3-bromo-4-methylbenzoate in the step 2, the objective compound wasprepared. Colorless crystal

¹H-NMR (D₂O)δ: 2.88(3H, s), 3.54(8H, br), 3.80(3H, s), 4.41(2H, s),7.39(1H, d), 7.52(2H, m)

REFERENCE EXAMPLE 22 3,5-dibromo-4-(4-methylpiperazin-1-ylmethyl)benzoylChloride Dihydrochloride

In the same manner as in Reference Example 1 (steps 2 to 5), except thatmethyl 3,5-dibromo-4-methylbenzoate was used in place of ethyl3-bromo-4-methylbenzoate in the step 2, the objective compound wasprepared.

Pale Orange Crystal

H-NMR (D₂O)δ: 2.89(3H, s), 3.73(8H, br), 4.73(2H, s), 8.19(2H, s)

REFERENCE EXAMPLE 233,5-dimethoxy-4-(4-methylpiperazin-1-ylmethyl)benzoyl ChlorideDihydrochloride

In the same manner as in Reference Example 1, except that3,5-dimethoxy-4-methylbenzoic acid was used in place of3-bromo-4-methylbenzoic acid in the step 1, the objective compound wasprepared.

Pale Yellow Crystal

¹H-NMR (D₂O)δ: 2.92(3H, s), 3.58(8H, br), 3.82(6H, s), 4.44(2H, s),7.20(2H, s)

REFERENCE EXAMPLE 243-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)benzoylchloride dihydrochloride

Step 1

Ethyl 3-(N,N-dimethylcarbamoyl)-4-methylbenzoate

This compound was prepared by version of the method described in thedocument (Org. Lett., 2002, 4, 2849-2851.). 1.00 g of ethyl3-iodo-4-methylbenzoate (intermediate of Reference Example 2) wasdissolved in 30 ml of N,N-dimethylformamide and 23 mg oftris(dibenzylideneacetone)dipalladium (0) was added. Under stirring atroom temperature, 643 μl of phosphorus oxychloride was added, followedby stirring with heating at 120° C. for 12 hours under an argonatmosphere. The reaction solution was mixed with an aqueous saturatedsodium hydrogen carbonate solution, extracted twice with ethyl acetate,washed with saturated saline and dried over anhydrous magnesium sulfate,and then the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain 338mg of the objective compound as a brown oily product.

¹H-NMR(CDCl₃)δ: 1.38(3H, t), 2.35(3H, s), 2.84(3H, s), 3.15(3H, s),4.36(2H, q), 7.29(1H, d), 7.87(1H, d), 7.95(1H, dd)

Step 2

Ethyl 4-(bromomethyl)-3-(N,N-dimethylcarbamoyl)benzoate

In the same manner as in Reference Example 1 (step 2), except that ethyl3-(N,N-dimethylcarbamoyl)-4-methylbenzoate obtained in the step 1 wasused in place of ethyl 3-bromo-4-methylbenzoate, the objective compoundwas prepared.

Yellow Oily Product

¹H-NMR(CDCl₃)δ: 1.38(3H, t), 2.91(3H, s), 3.18(3H, s), 4.36(2H, q),4.60(2H,. S), 7.51(1H, d), 7.88(1H, d), 7.98(1H, dd)

Step 3

Ethyl 3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)benzoate

In the same manner as in Reference Example 1 (step 3), except that ethyl4-(bromomethyl)-3-(N,N-dimethylcarbamoyl)benzoate obtained in the step 2was used in place of ethyl 3-bromo-4-(bromomethyl)benzoate, theobjective compound was prepared.

Brown Oily Product

¹H-NMR(CDCl₃)δ: 1.39(3H, t), 2.28(3H, s), 2.46(8H, br), 2.86(3H, s),3.13(3H, s), 3.58(2H, br), 4.37(2H, q), 7.45(1H, d), 7.86(1H, d),7.97(1H, dd)

Step 4

3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)benzoic AcidDihydrochloride

In the same manner as in Reference Example 1 (step 4), except that ethyl3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)benzoateobtained in the step 3 was used in place of ethyl3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoate, the objective compoundwas prepared.

Pale Yellow Amorphous

¹H-NMR (D₂O)δ: 2.83(3H, s), 2.87(3H, s), 3.02(3H, s), 3.44(8H, br),4.28(2H, s), 7.63(1H, d), 7.97(1H, d), 8.05(1H, dd)

Step 5

3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)benzoylChloride Dihydrochloride

In the same manner as in Reference Example 1 (step 5), except that3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)benzoic aciddihydrochloride obtained in the step 4 was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochloride,the objective compound was prepared.

Pale Orange Crystal

¹H-NMR (D₂O)δ: 2.83(3H, s), 2.87(3H, s), 3.03(3H, s), 3.47(8H, br),4.29(2H, s), 7.64(1H, d), 7.99(1H, d), 8.06(1H, dd)

REFERENCE EXAMPLE 25 3-bromo-4-(4-ethylpiperazin-1-ylmethyl)benzoylChloride Dihydrochloride

In the same manner as in Reference Example 1, except thatN-ethylpiperazine was used in place of N-methylpiperazine in the step 3,the objective compound was prepared.

Pale Brown Crystal

¹H-NMR (D₂O)δ: 1.33(3H, t), 3.34(2H, q), 3.67(8H, br), 4.73(2H, s),7.73(1H, d), 8.03(1H, dd), 8.32(1H, d)

REFERENCE EXAMPLE 26 3-bromo-4-[4-(n-propyl)piperazin-1-ylmethyl]benzoylChloride Dihydrochloride

In the same manner as in Reference Example 1, except thatN-(n-propyl)piperazine was used in place of N-methylpiperazine in thestep 3, the objective compound was prepared.

Colorless Crystal

¹H-NMR (D₂O)δ: 0.95(3H, t), 1.75(2H, m), 3.23(2H, m), 3.79(8H, br),4.73(2H, s), 7.73(1H, d), 8.05(1H, dd), 8.35(1H, d)

REFERENCE EXAMPLE 27 3-bromo-4-(N,N-dimethylaminomethyl)benzoyl ChlorideDihydrochloride

In the same manner as in Reference Example 1, except that dimethylaminewas used in place of N-methylpiperazine in the step 3, the objectivecompound was prepared.

Colorless Crystal

¹H-NMR (D₂O)δ: 2.80(6H, d), 4.41(2H, s), 7.53(1H, d), 7.88(1H, dd),8.16(1H, d)

REFERENCE EXAMPLE 28 3-bromo-4-(N,N-diethylaminomethyl)benzoyl ChlorideDihydrochloride

In the same manner as in Reference Example 1, except that diethylaminewas used in place of N-methylpiperazine in the step 3, the objectivecompound was prepared.

Colorless Crystal

¹H-NMR (D₂O)δ: 1.34(6H, t), 3.29(4H, q), 4.52(2H, s), 7.65(1H, d),7.99(1H, dd), 8.26(1H, d)

REFERENCE EXAMPLE 29 3-bromo-4-(1-pyrrolidinylmethyl)benzoyl ChlorideDihydrochloride

In the same manner as in Reference Example 1, except that pyrrolidinewas used in place of N-methylpiperazine in the step 3, the objectivecompound was prepared.

Pale Brown Crystal

¹H-NMR (D₂O)δ: 1.95(4H, m), 3.16(2H, m), 3.46(2H, m), 4.47(2H, s),7.54(1H, d), 7.88(1H, d), 8.17(1H, s)

REFERENCE EXAMPLE 30 3-bromo-4-(piperidinomethyl)benzoyl ChlorideDihydrochloride

In the same manner as in Reference Example 1, except that piperidine wasused in place of N-methylpiperazine in the step 3, the objectivecompound was prepared.

Colorless Crystal

¹H-NMR (D₂O)δ: 1.69(6H, m), 3.14(2H, t), 3.53(2H, d), 4.50(2H, s),7.66(1H, d), 8.00(1H, d), 8.29(1H, s)

REFERENCE EXAMPLE 31 3-bromo-4-(morpholinomethyl)benzoyl ChlorideDihydrochloride

In the same manner as in Reference Example 1, except that morpholine wasused in place of N-methylpiperazine in the step 3, the objectivecompound was prepared.

Pink Crystal

¹H-NMR (D₂O)δ: 3.39(4H, m), 3.69(2H, m), 3.99(2H, m), 4.51(2H, s),7.60(1H, d), 7.92(1H, dd), 8.22(1H, s)

REFERENCE EXAMPLE 323-bromo-4-(cis-3,5-dimethylpiperazin-1-ylmethyl)benzoic AcidDihydrochloride

In the same manner as in Reference Example 1 (steps 1 to 4), except thatcis-2,6-dimethylpiperazine was used in place of N-methylpiperazine inthe step 3, the objective compound was prepared.

Colorless Crystal

¹H-NMR (D₂O)δ: 1.25(6H, d), 3.11(2H, t), 3.62(4H, m), 4.53(2H, s),4.73(2H, s), 7.59(1H, d), 7.90(1H, dd), 8.20(1H, d)

REFERENCE EXAMPLE 333-bromo-4-(4-methyl-hexahydro-1H-1,4-diazepin-1-ylmethyl)benzoic AcidDihydrochloride

In the same manner as in Reference Example 1 (steps 1 to 4), except that4-methyl-hexahydro-1H-1,4-diazepine was used in place ofN-methylpiperazine in the step 3, the objective compound was prepared.

Yellow Crystal

¹H-NMR (D₂O)δ: 2.23(2H, br), 2.88(3H, s), 3.57(4H, br), 3.74(4H, s),4.58(2H, s), 7.61(1H, d), 7.90(1H, dd), 8.17(1H, d)

REFERENCE EXAMPLE 343-bromo-4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]benzoic Acid

Step 1

Ethyl 3-bromo-4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]benzoate

1.00 g of ethyl 3-bromo-4-(bromomethyl)benzoate (intermediate ofReference Example 1) was dissolved in 10 ml of anhydrous tetrahydrofuranand, after adding 473 mg of potassium carbonate, 467 mg ofN-(t-butoxycarbonyl)piperazine was added dropwise while stirring at roomtemperature under an argon atmosphere. After stirring at roomtemperature for 20 hours, insolubles were removed by filtration and thesolvent in the filtrate was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain 918mg of the objective compound as a pale yellow oily product.

¹H-NMR(CDCl₃)δ: 1.40(3H, t), 1.46(9H, s), 2.47(4H, t), 3.45(4H, m),3.63(2H, s), 4.38(2H, q), 7.58(1H, d), 7.96(1H, dd), 8.21(1H, d)

Step 2

3-bromo-4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]benzoic Acid

898 mg of ethyl3-bromo-4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]benzoate obtained inthe step 1 was dissolved in 5 ml of methanol and 3.2 ml of an aqueous 1Nsodium hydroxide solution was added. After stirring at room temperaturefor 3 hours, the mixture was neutralized by slowly adding 3.2 ml of a 1Nhydrochloric acid. The deposited crystal was collected by filtration,washed with water and then dried under reduced pressure to obtain 796 mgof the objective compound as a colorless crystal.

Melting point: 204-205° C. (with decomposition)

¹H-NMR (DMSO-d₆)δ: 1.40(9H, s), 2.40(4H, t), 3.36(4H, m), 3.61(2H, s),7.63(1H, d), 7.92(1H, dd), 8.07(1H, d)

REFERENCE EXAMPLE 354-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]-3-trifluoromethylbenzoicAcid

In the same manner as in Reference Example 34, except that ethyl4-(bromomethyl)-3-trifluoromethylbenzoate (intermediate of ReferenceExample 5) was used in place of ethyl 3-bromo-4-(bromomethyl)benzoate inthe step 1, the objective compound was prepared.

Colorless Crystal

Melting point: 126-134° C.

¹H-NMR(CDCl₃)δ: 1.47(9H, s), 2.55(4H, br), 3.54(4H, br), 3.84(2H, s),8.05(1H, d), 8.25(1H, d), 8.37(1H, s)

EXAMPLE 13-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

0.74 g of 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was dissolved in 27ml of anhydrous pyridine and 920 mg of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride(Reference Example 1) was added, followed by stirring at roomtemperature for 14 hours. The reaction solution was mixed with ice waterand aqueous saturated sodium hydrogen carbonate solution and thenextracted with ethyl acetate. The extract was washed with water anddried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography to obtain 1.48 g of a crude product. The crudeproduct was crystallized by adding chloroform-diethyl ether (1:1) andthe crystal was collected by filtration to obtain 1.05 g of theobjective compound as a colorless crystal.

Melting point: 202-203° C. (with decomposition)

Elemental analysis (for C₂₉H₃₀BrN₇O.0.9H₂O)

Calcd. (%): C, 59.17; H, 5.44; N, 16.65. Found (%): C, 59.16; H, 5.21;N, 16.64

EXAMPLE 23-iodo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 1, exceptthat 3-iodo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride (Reference Example 2) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the reaction was conducted at room temperaturefor 24 hours and the resulting crystal was recrystallized from methanol.

Colorless Crystal

Melting point: 199-200° C. (with decomposition)

Elemental analysis (for C₂₉H₃₀IN₇O)

Calcd. (%): C, 56.23; H, 4.88; N, 15.83. Found (%): C, 56.13; H, 4.94;N, 15.80

EXAMPLE 33-chloro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 1, exceptthat 3-chloro-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride (Reference Example 3) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the reaction was conducted at room temperaturefor 24 hours.

Colorless Crystal

Melting point: 193-194° C. (with decomposition)

Elemental analysis (for C₂₉H₃₀ClN₇O.0.6H₂O)

Calcd. (%): C, 64.64; H, 5.84; N, 18.20. Found (%): C, 64.62; H, 5.60;N, 18.23

EXAMPLE 43-fluoro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 1, exceptthat 3-fluoro-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride (Reference Example 4) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the reaction was conducted at room temperaturefor 22 hours and the crude crystal obtained by purification with silicagel column chromatography was washed with chloroform-diethyl ether(1:1).

Colorless Crystal

Melting point: 197-199° C. (with decomposition)

Elemental analysis (for C₂₉H₃₀FN₇O.0.3H₂O)

Calcd. (%): C, 67.37; H, 5.97; N, 18.96. Found (%): C, 67.36; H, 5.96;N, 18.93

EXAMPLE 54-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 1, exceptthat 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloridedihydrochloride (Reference Example 5) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, that the reaction was conducted at room temperature for22 hours and the resulting crystal was washed with diethyl ether.

Colorless Crystal

Melting point: 182-183° C. (with decomposition)

Elemental analysis (for C₃₀H₃₀F₃N₇O.0.3H₂O)

Calcd. (%): C, 63.55; H, 5.44; N, 17.29. Found (%): C, 63.43; H, 5.37;N, 17.29

EXAMPLE 64-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 1, exceptthat 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloridedihydrochloride (Reference Example 5) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochlorideand 4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (ReferenceExample 6) was used in place of4-methyl-3-[4-(3-pyridinyl)pyrimidin-2-ylamino]aniline, and that thereaction was conducted at room temperature for 20 hours and the crudecrystal obtained by purification with silica gel column chromatographywas washed with diethyl ether.

Pale Yellow Crystal

Melting point: 231-233° C. (with decomposition)

Elemental analysis (for C₂₉H₂₉F₃N₈O.0.2H₂O)

Calcd. (%): C, 61.52; H, 5.23; N, 19.79. Found (%): C, 61.37; H, 5.24;N, 19.81

EXAMPLE 73-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(2-pyrazinyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 1, exceptthat 4-methyl-3-[4-(2-pyrazinyl)pyrimidin-2-ylamino]aniline (ReferenceExample 7) was used in place of4-methyl-3-[4-(3-pyridinyl)pyrimidin-2-ylamino]aniline, and that thereaction was conducted at room temperature for 18 hours.

Pale Yellow Crystal

Melting point: 213-214° C. (with decomposition)

Elemental analysis (for C₂₈H₂₉BrN₈O)

Calcd. (%): C, 58.64; H, 5.10; N, 19.54. Found (%): C, 58.41; H, 5.11;N, 19.24

EXAMPLE 83-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamide

629 mg of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline(Reference Example 8) was suspended in 7 ml of acetonitrile, and then 24mg of 4-dimethylaminopyridine and 1.15 ml ofN,N-diisopropyl-N-ethylamine were added in turn. Under ice-coolstirring, 979 mg of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoylchloride dihydrochloride (Reference Example 1) was added by fiveportions, followed by stirring at room temperature for one hour afterremoving an ice bath. The reaction solution was mixed with water,extracted with chloroform and then dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure and theresidue was purified by silica gel column chromatography. The resultingcrude crystal was washed in turn with ethyl acetate and diethyl etherand the crystal was collected by filtration to obtain 939 mg of theobjective compound as a pale yellow crystal.

Melting point: 219-222° C. (with decomposition)

Elemental analysis (for C₂₉H₂₉BrClN₇O)

Calcd. (%): C, 57.39; H, 4.82; N, 16.15

Found (%): C, 57.07; H, 4.75; N, 16.09 EXAMPLE 93-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline(Reference Example 9) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline, andthat the crude crystal obtained by purification with silica gel columnchromatography was recrystallized from ethyl acetate-diethyl ether.

Pale Yellow Crystal

Melting point: 194-195° C. (with decomposition)

Elemental analysis (for C₂₉H₂₉Br₂N₇O.0.3H₂O)

Calcd. (%): C, 53.03; H, 4.54; N, 14.93. Found (%): C, 53.07; H, 4.53;N, 14.70

EXAMPLE 104-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline(Reference Example 9) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloridedihydrochloride (Reference Example 5) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding diisopropyl ether-ethylacetate.

Pale Yellow Crystal

Melting point: 171-173° C. (with decomposition) Elemental analysis (forC₃₀H₂₉BrF₃N₇O.0.7H₂O)

Calcd. (%): C, 55.17; H, 4.69; N, 15.01. Found (%): C, 55.16; H, 4.57;N, 14.94

EXAMPLE 113-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(1,2-dihydropyridazin-4-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat3-[4-(1,2-dihydropyridazin-4-yl)pyrimidin-2-ylamino]-4-methylaniline(Reference Example 10) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline, andthat extraction was conducted with ethyl acetate and the residueobtained by purification with silica gel column chromatography waswashed with diisopropyl ether.

Pale Yellow Amorphous

Elemental analysis (for C₂₈H₃₁BrN₈O.0.8{(CH₃)₂CH}₂O)

Calcd. (%): C, 59.94; H, 6.47; N, 17.05. Found (%): C, 59.51; H, 6.30;N, 16.80

EXAMPLE 123-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridazinyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridazinyl)pyrimidin-2-ylamino]aniline (ReferenceExample 11) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline, andthat the crude crystal obtained by purification with silica gel columnchromatography was washed with ethyl acetate-chloroform.

Pale Yellow Crystal

Melting point: 185-187° C. (with decomposition)

Elemental analysis (for C₂₈H₂₉BrN₈O.0.1H₂O)

Calcd. (%): C, 58.28; H, 5.13; N, 19.42. Found (%): C, 58.24; H, 5.00;N, 19.48

EXAMPLE 133-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

150 mg of 4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline(Reference Example 6) was dissolved in 4 ml of N,N-dimethylformamide,and then 255 mg of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic aciddihydrochloride (Reference Example 1) and 109 mg of triethylamine wereadded in turn. While stirring the suspension at room temperature, 106 mgof diethyl cyanophosphonate and 55 mg of triethylamine were added inturn, followed by stirring at room temperature for 3 hours. After thesolvent was distilled off under reduced pressure, the residue was mixedwith water and an aqueous saturated sodium hydrogen carbonate solutionand then extracted with chloroform. The extract was washed with waterand dried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography to obtain 240 mg of a crude product. The crudeproduct was dissolved in chloroform-methanol and 2-propanol was added,followed by concentration under reduced pressure. The deposited crystalwas collected by filtration and washed in turn with 2-propanol anddiethyl ether to obtain 147 mg of the objective compound as a paleyellow crystal.

Melting point: 238-240° C. (with decomposition)

Elemental analysis (for C₂₈H₂₉BrN₈O.0.1H₂O)

Calcd. (%): C, 58.46; H, 5.12; N, 19.48. Found (%): C, 58.21; H, 5.02;N, 19.30

EXAMPLE 143-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyridin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyridin-2-ylamino]aniline (ReferenceExample 12) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline, andthat the crude crystal obtained by purification with silica gel columnchromatography was washed with ethyl acetate-chloroform-methanol.

Pale Yellow Crystal

Melting point: 244-245° C. (with decomposition)

Elemental analysis (for C₃₀H₃₁BrN₆O.0.6H₂O)

Calcd. (%): C, 61.88; H, 5.57; N, 14.43. Found (%): C, 61.71; H, 5.49;N, 14.13

EXAMPLE 153-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(5-pyrimidinyl)pyridin-2-ylamino]aniline (ReferenceExample 13) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline, andthat the crude crystal obtained by purification with silica gel columnchromatography was washed with ethyl acetate-diethyl ether.

Pale Yellow Crystal

Melting point: 244-246° C. (with decomposition)

Elemental analysis (for C₂₉H₃₀BrN₇O.0.2H₂O.0.2CH₃COOC₂H₅)

Calcd. (%): C, 60.28; H, 5.43; N, 16.51. Found (%): C, 60.12; H, 5.40;N, 16.28

EXAMPLE 163-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyridin-6-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[2-(3-pyridyl)pyridin-6-ylamino]aniline (ReferenceExample 14) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline, andthat the crude product purified by silica gel column chromatography wasnot further washed.

Pale Yellow Amorphous

Elemental analysis (for C₃₀H₃₁BrN₆O.1.5H₂O)

Calcd. (%): C, 60.20; H, 5.73; N, 14.04 Found (%): C, 60.39; H, 5.55; N,13.00

FAB-MS (Pos.) m/z 571, (Neg.) m/z 569

EXAMPLE 173-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)pyridin-5-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[3-(3-pyridyl)pyridin-5-ylamino]aniline (ReferenceExample 15) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline, andthat extraction was conducted with ethyl acetate and the oily productpurified by silica gel column chromatography was crystallized by addingethyl acetate-diethyl ether.

Pale Yellow Crystal

Melting point: 139-141° C.

Elemental analysis (for C₃₀H₃₁BrN₆O.1.2H₂O)

Calcd. (%): C, 60.75; H, 5.68; N, 14.17. Found (%): C, 60.96; H, 5.62;N, 13.98

EXAMPLE 183-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)phenylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[3-(3-pyridyl)phenylamino]aniline (Reference Example 16)was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline, andthat extraction was conducted with ethyl acetate and the oily productpurified by silica gel column chromatography was crystallized by addingethyl acetate-hexane.

Pale Brown Crystal

Melting point: 174-175° C.

Elemental analysis (for C₃₁H₃₂BrN₅O)

Calcd. (%): C, 65.26; H, 5.65; N, 12.28. Found (%): C, 65.12; H, 5.73;N, 12.19

EXAMPLE 193-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino]aniline (ReferenceExample 17) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline, andthat extraction was conducted with ethyl acetate and the amorphouspurified by silica gel column chromatography was crystallized by addingethyl acetate.

Yellow Crystal

Melting point: 192-193° C.

Elemental analysis (for C₂₉H₃₀BrN₇O.0.25H₂O)

Calcd. (%): C, 60.37; H, 5.33; N, 16.99. Found (%): C, 60.58; H, 5.35;N, 16.76

EXAMPLE 203-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[5-(3-pyridyl)-1,2,4-triazin-3-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[5-(3-pyridyl)-1,2,4-triazin-3-ylamino]aniline(Reference Example 18) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline, andthat the amorphous purified by silica gel column chromatography wascrystallized by adding 2-propanol.

Yellow Crystal

Melting point: 219-221° C.

Elemental analysis (for C₂₈H₂₉BrN₈O.1.2H₂O.0.1CH₃CH(OH)CH₃)

Calcd. (%): C, 56.55; H, 5.40; N, 18.64. Found (%): C, 56.58; H, 5.00;N, 18.27

EXAMPLE 213-methyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and3-methyl-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride (Reference Example 19) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding ethyl acetate.

Pale Yellow Crystal

Melting point: 192-193° C.

Elemental analysis (for C₃₀H₃₃N₇O)

Calcd. (%): C, 70.98; H, 6.55; N, 19.31. Found (%): C, 70.79; H, 6.67;N, 19.39

EXAMPLE 224-(4-methylpiperazin-1-ylmethyl)-3-nitro-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and4-(4-methylpiperazin-1-ylmethyl)-3-nitrobenzoyl chloride dihydrochloride(Reference Example 20) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that extraction was conducted with ethyl acetateand the oily product purified by silica gel column chromatography wascrystallized by adding ethyl acetate-diethyl ether.

Pale Yellow Crystal

Melting point: 184-186° C.

Elemental analysis (for C₂₉H₃₀N₈O₃.0.7H₂O)

Calcd. (%): C, 63.19; H, 5.74; N, 20.33. Found (%): C, 63.38; H, 5.57;N, 20.00

EXAMPLE 233-methoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and3-methoxy-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride (Reference Example 21) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding ethyl acetate and then washedwith diethyl ether.

Pale Yellow Crystal

Melting point: 171-172° C. (with decomposition) Elemental analysis (forC₃₀H₃₃N₇O₂.0.6H₂O)

Calcd. (%): C, 67.42; H, 6.45; N, 18.35. Found (%): C, 67.23; H, 6.36;N, 18.19

EXAMPLE 243,5-dibromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and3,5-dibromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride (Reference Example 22) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding ethyl acetate and then washedwith diethyl ether.

Pale Yellow Crystal

Melting point: 227-229° C.

Elemental analysis (for C₂₉H₂₉Br₂N₇O.0.1H₂O.0.35CH₃CO₂C₂H₅)

Calcd. (%): C, 53.38; H, 4.72; N, 14.33. Found (%): C, 53.02; H, 4.74;N, 14.09

EXAMPLE 253,5-dimethoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and3,5-dimethoxy-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride (Reference Example 23) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding ethyl acetate.

Yellow Crystal

Melting point: 201-214° C. (with decomposition)

Elemental analysis (for C₃₁H₃₅N₇O₃.0.5H₂O)

Calcd. (%): C, 66.17; H, 6.45; N, 17.43. Found (%): C, 65.91; H, 6.42;N, 17.42

EXAMPLE 263-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 1, exceptthat 3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)benzoylchloride dihydrochloride (Reference Example 24) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding ethyl acetate.

Orange Crystal

Melting point: 210-214° C. (with decomposition) Elemental analysis (forC₃₂H₃₆N₈O₂.0.6H₂O)

Calcd. (%): C, 66.79; H, 6.52; N, 19.47. Found (%): C, 66.41; H, 6.17;N, 19.36

EXAMPLE 273-bromo-4-(4-ethylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and3-bromo-4-(4-ethylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride(Reference Example 25) was used in place of3-bromo.-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding ethyl acetate.

Pale Yellow Crystal

Melting point: 202-203° C.

Elemental analysis (for C₃₀H₃₂BrN₇O.0.25H₂O)

Calcd. (%): C, 60.97; H, 5.54; N, 16.59. Found (%): C, 60.96; H, 5.54;N, 16.32

EXAMPLE 283-bromo-4-[4-(n-propyl)piperazin-1-ylmethyl]-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and3-bromo-4-[4-(n-propyl)piperazin-1-ylmethyl]benzoyl chloridedihydrochloride (Reference Example 26) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding ethyl acetate.

Pale Yellow Crystal

Melting point: 204-205° C.

Elemental analysis (for C₃₁H₃₄BrN₇O.0.4H₂O)

Calcd. (%): C, 61.26; H, 5.77; N, 16.13. Found (%): C, 61.48; H, 5.66;N, 15.79

EXAMPLE 293-bromo-4-(N,N-dimethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and3-bromo-4-(N,N-dimethylaminomethyl)benzoyl chloride dihydrochloride(Reference Example 27) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding ethyl acetate.

Colorless Crystal

Melting point: 154-155° C.

Elemental analysis (for C₂₆H₂₅BrN₆O)

Calcd. (%): C, 60.35; H, 4.87; N, 16.24. Found. (%): C, 60.20; H, 4.97;N, 16.13

EXAMPLE 303-bromo-4-(N,N-diethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and3-bromo-4-(N,N-diethylaminomethyl)benzoyl chloride dihydrochloride(Reference Example 28) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding ethyl acetate.

Pale Yellow Crystal

Melting point: 172-173° C.

Elemental analysis (for C₂₈H₂₉BrN₆O)

Calcd. (%): C, 61.65; H, 5.36; N, 15.41 Found (%): C, 61.35; H, 5.36; N,15.35

EXAMPLE 313-bromo-4-(1-pyrrolidinylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and3-bromo-4-(1-pyrrolidinylmethyl)benzoyl chloride dihydrochloride(Reference Example 29) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding ethyl acetate.

Pale Yellow Crystal

Melting point: 195-196° C.

Elemental analysis (for C₂₈H₂₇BrN₆O)

Calcd. (%): C, 61.88; H, 5.01; N, 15.46. Found (%): C, 61.68; H, 5.12;N, 15.11

EXAMPLE 323-bromo-4-(piperidinomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and3-bromo-4-(piperidinomethyl)benzoyl chloride dihydrochloride (ReferenceExample 30) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding ethyl acetate.

Pale Yellow Crystal

Melting point: 158-159° C.

Elemental analysis (for C₂₉H₂₉BrN₆O)

Calcd. (%): C, 62.48; H, 5.24; N, 15.07. Found (%): C, 62.23; H, 5.25;N, 14.83

EXAMPLE 333-bromo-4-(morpholinomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 8, exceptthat 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) was used in place of3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline and3-bromo-4-(morpholinomethyl)benzoyl chloride dihydrochloride (ReferenceExample 31) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloridedihydrochloride, and that the oily product purified by silica gel columnchromatography was crystallized by adding ethyl acetate.

Pale Yellow Crystal

Melting point: 179-180° C.

Elemental analysis (for C₂₈H₂₉BrN₆O₂)

Calcd. (%): C, 60.11; H, 4.86; N, 15.02. Found (%): C, 59.94; H, 4.93;N, 14.96

EXAMPLE 343-bromo-4-(cis-3,5-dimethylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared by version of the method described in thedocument (Synthesis, 1982, 288-291.). To 356 mg of4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (JapaneseUnexamined Patent Publication (Kokai) No. 6-87834) and 770 mg of3-bromo-4-(cis-3,5-dimethylpiperazin-1-ylmethyl)benzoic aciddihydrochloride (Reference Example 32), 7 ml of dichloromethane and 715μl of triethylamine were added in turn. Under stirring at roomtemperature, 446 mg of phenyl N-phenylphosphoramidochloridate(Synthesis, 1982, 288-291.) was added, following by stirring at roomtemperature for 2 hours. The reaction solution was mixed with water andthen extracted twice with chloroform. The extract was washed with anaqueous saturated sodium hydrogen carbonate solution and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified in turn by silica gelcolumn chromatography and NH— silica gel column chromatography and theresulting oily product was crystallized from ethyl acetate. The crystalwas washed with diethyl ether to obtain 259 mg of the objective compoundas a pale yellow crystal.

Melting point: 204-205° C.

Elemental analysis (for C₃₀H₃₂BrN₇O)

Calcd. (%): C, 61.43; H, 5.50; N, 16.72. Found (%): C, 61.19; H, 5.48;N, 16.49

EXAMPLE 353-bromo-4-(4-methyl-hexahydro-1H-1,4-diazepin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 34, exceptthat 3-bromo-4-(4-methyl-hexahydro-1H-1,4-diazepin-1-ylmethyl)benzoicacid dihydrochloride (Reference Example 33) was used in place of3-bromo-4-(cis-3,5-dimethylpiperazin-1-ylmethyl)benzoic aciddihydrochloride.

Pale Yellow Crystal

Melting point: 156-157° C.

Elemental analysis (for C₃₀H₃₂BrN₇O)

Calcd. (%): C, 61.43; H, 5.50; N, 16.72. Found (%): C, 61.13; H, 5.43;N, 16.39

EXAMPLE 363-bromo-4-(1-piperazinylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

First,3-bromo-4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamidewas prepared by version of the method described in document (Synthesis,1982, 288-291.). In the same manner as in Example 34, except that4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (ReferenceExample 6) was used in place of4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline and3-bromo-4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]benzoic acid(Reference Example 34) was used in place of3-bromo-4-(cis-3,5-dimethylpiperazin-1-ylmethyl)benzoic aciddihydrochloride, and that extraction was conducted with ethyl acetateand the extract was purified only by silica gel column chromatographyand then used for the subsequent reaction without being purifiedfurthermore. Then,3-bromo-4-(1-piperazinylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamidewas prepared. To 187 mg of the reaction crude product above, 1.5 ml oftrifluoroacetic acid was added, followed by stirring at room temperaturefor 2 hours. The reaction solution was alkalified by adding an aqueous10% sodium hydroxide solution and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by NH-silica gel column chromatography andcrystallized by adding ethyl acetate. The crystal was washed with warmedethyl acetate to obtain 49 mg of the objective compound as a pale yellowcrystal.

Pale Yellow Crystal

Melting point: 225-228° C. (with decomposition)

Elemental analysis (for C₂₇H₂₇BrN₈O.0.3H₂O)

Calcd. (%): C, 57.41; H, 4.92; N, 19.84. Found (%): C, 57.53; H, 5.11;N, 18.92

FAB-MS (Pos.) m/z 559

EXAMPLE 374-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

This compound was prepared in the same manner as in Example 34, exceptthat 4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (ReferenceExample 6) was used in place of4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline and4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]-3-trifluoromethylbenzoicacid (Reference Example 35) was used in place of3-bromo-4-(cis-3,5-dimethylpiperazin-1-ylmethyl)benzoic aciddihydrochloride, and that extraction was conducted with ethyl acetateand the oily product purified by silica gel column chromatography wascrystallized by adding ethanol and then washed in turn with ethanol anddiethyl ether.

Pale Yellow Crystal

Melting point: 188-191° C.

¹H-NMR(CDCl₃)δ: 1.47(9H, s), 2.36(3H, s), 2.43(4H, t), 3.45(4H, t),3.71(2H, s), 7.09(1H, br), 7.18(1H, d), 7.23(2H, s), 7.95(1H, d),8.05(2H, d), 8.14(1H, s), 8.56(1H, d), 8.65(1H, br), 9.30(1H, s),9.42(2H, s)

EXAMPLE 384-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

To 1.00 g of4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide(Example 37), 8 ml of trifluoroacetic acid was added, followed bystirring at room temperature for 2 hours. The reaction solution wasalkalified by adding an aqueous 10% sodium hydroxide solution anddichloromethane was added. The deposited crystal was collected byfiltration to obtain 530 mg of a crude crystal. The filtrate wasextracted twice with dichloromethane, dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressureto obtain 370 mg of a crude crystal. 900 mg of both crude crystals werecombined, purified by NH-silica gel column chromatography and thencrystallized by adding isopropanol. The crystal was washed in turn withethyl acetate and diethyl ether to obtain 258 mg of the objectivecompound as a pale yellow crystal.

Pale Yellow Crystal

Melting point: 208-211° C.

Elemental analysis (for C₂₈H₂₇F₃N₈O)

Calcd. (%): C, 61.31; H, 4.96; N, 20.43. Found (%): C, 61.03; H, 5.01;N, 20.33

EXAMPLE 393-methoxycarbonyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

100 mg of3-iodo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide(Example 2), 1 mg of dichlorobis(triphenylphosphine)palladium (II) and20 mg of sodium hydrogen carbonate were suspended in 5 ml of anhydrousmethanol and the suspension was heated at reflux at a bath temperatureof 80° C. for 2 hours while bubbling a carbon monoxide gas into thereaction solution. After air cooling, water and ethyl acetate were addedto the reaction solution and insolubles were removed by filtration, andthen the filtrate was extracted with ethyl acetate. The extract waswashed with water and dried over anhydrous magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography and crystallized by addingethyl acetate-diethyl ether to obtain 64 mg of the objective compound asa colorless crystal.

Melting point: 159-161° C. (with decomposition)

Elemental analysis (for C₃₁H₃₃N₇O₃.0.2H₂O)

Calcd. (%): C, 67.06; H, 6.06; N, 17.66. Found (%): C, 66.77; H, 6.03;N, 17.68

EXAMPLE 403-cyano-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide

200 mg of3-iodo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide(Example 2), 35 mg of tetrakis(triphenylphosphine)palladium (0) and 45mg of 60% zinc cyanide were suspended in 2 ml of anhydrousN,N-dimethylformamide, followed by stirring with heating at 80° C. for24 hours. After air drying, the reaction solution was mixed with anaqueous saturated sodium hydrogen carbonate solution and extracted twicewith chloroform. The extract was dried over anhydrous magnesium sulfateand the solvent was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography and crystallized byadding ethanol to obtain 34 mg of the objective compound as a paleyellow crystal.

Melting point: 191-193° C. (with decomposition)

Elemental analysis (for C₃₀H₃₀N₈O.0.5H₂O)

Calcd. (%): C, 68.29; H, 5.92; N, 21.24. Found (%): C, 68.05; H, 5.99;N, 21.12

EXAMPLE 413-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamidehydrochloride

5.00 g of3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide(Example 13) was suspended in 250 ml of an aqueous 50% ethanol solutionand 9.24 ml of 1N hydrochloric acid was added, followed by stirring withheating in a hot bath at 80° C. to obtain a homogeneous solution. Thereaction solution was filtered with heating and the solvent in thefiltrate was distilled off under reduced pressure. The residue wasdissolved with heating in 30 ml of ethanol and then allowed to stand atroom temperature for one day. The deposited crystal was collected byfiltration and washed with ethanol to obtain 5.13 g of the objectivecompound as a pale yellow crystal.

Melting point: 184-186° C. (with decomposition)

Elemental analysis (for C₂₈H₂₉BrN₈O.1.0HCl.2.0H₂O)

Calcd. (%): C, 52.06; H, 5.31; N, 17.35. Found (%): C, 51.72; H, 5.17;N, 17.21

EXAMPLE 424-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamidehydrochloride

This compound was prepared in the same manner as in Example 41, exceptthat4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide(Example 6) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide.

Pale Yellow Crystal

Melting point: 2.44-246° C. (with decomposition)

Elemental analysis (for C₂₉H₂₉F₃N₈O.1.0HCl.0.8H₂O)

Calcd. (%): C, 56.78; H, 5.19; N, 18.27. Found (%): C, 56.80; H, 4.96;N, 18.49

EXAMPLE 434-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamidehydrochloride

This compound was prepared in the same manner as in Example 41, exceptthat4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamide(Example 10) was used in place of3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide.

Pale Yellow Crystal

Melting point: 184-187° C.

Elemental analysis (for C₃₀H₂₉BrF₃N₇O.1.0HCl.1.0H₂O)

Calcd. (%): C, 51.85; H, 4.64; N, 14.11. Found (%): C, 51.78; H, 4.74;N, 13.92

EXAMPLE 444-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamidemethanesulfonate

7.00 g of4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide(Example 6) was suspended in 70 ml of methanol and a solution of 1.20 gof methanesulfonic acid in 3 ml of methanol was added dropwise, followedby stirring with heating in an oil bath at 50° C. for 10 minutes. Thereaction solution was mixed with 700 mg of activated carbon (KyoryokuShirasagi MOIWY433) and then heated at reflux for 30 minutes. Thereaction solution was filtered with heating and the solvent in thefiltrate was distilled off under reduced pressure. The residue wasdissolved with heating in 10 ml of methanol and then allowed to stand atroom temperature for 10 minutes. As a result, the entire reactionsolution was solidified. The solution was crystallized by addingisopropanol to obtain 7.20 g of the objective compound as a pale yellowcrystal.

Melting point: 171-173° C.

Elemental analysis (for C₂₉H₂₉F₃N₈O.1.0CH₃SO₃H.1.0H₂O)

Calcd. (%): C, 53.25; H, 5.21; N, 16.56. Found (%): C, 53.04; H, 5.39;N, 16.74

TEST EXAMPLE 1

Cell Growth Inhibitory Effect

K562 cells and U937 cells (purchased from American Type CultureCollection) were cultured in a RPMI-1640 medium (manufactured by Sigma)containing 10% (v/v) fetal calf serum (FCS) (manufactures by Sigma)(RPMI-1640/FCS). K562 cells and U937 cells were seeded at a density of5000 cells/100 μl/well, respectively. The plate was incubated in a CO₂incubator overnight. A test drug was prepared with dimethylsulfoxide(DMSO) (manufactured by Nacalai Tesque) in the concentration 1000 timeshigher than the test concentration (0, 0.00001 to 1 μM). The resultingsolution was diluted 500 times in a RPMI-1640/FCS medium and then 100 μlof the diluent was added in a well. The plate was incubated in a CO₂incubator. After 72 hours, 20 μl of Cell counting Kit-8 (5 mmol/l WST-8,0.2 mmol/l 1-Methoxy PMS, 150 mmol/l NaCl) (manufactured by Dojindo) wasadded to each well. After reaction for color development in a CO₂incubator for 3 hours, an absorbance of formazan, generated by reductionof WST-8 was determined at 450 nm using Multi-level counter ARVOsx(manufactured by Wallac).

IC₅₀ value (in μM) was calculated from the following fomula:cell growth inhibition rate=100−(absorbance of wells withdrug/absorbance of wells with 0.1% DMSO)×100After log-logit transformation, the concentration that gave a cellgrowth inhibition rate of 50% as defined in IC₅₀, was calculated byleast square method. The results are shown in Table 1.

As a control drug,4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide(see Patent Document 1) was used. TABLE 1 Cell growth inhibitory effectK562 cells U937 cells Ratio (U937 (IC₅₀ value: (IC₅₀ value: cells/K562Test drugs μM) μM) cells) Example 1 0.0022 4.80 2181.8 Example 2 0.00233.34 1452.2 Example 3 0.0046 5.01 1089.1 Example 4 0.033 12.40 375.8Example 5 0.0008 3.99 4987.5 Example 6 0.0005 5.39 10780.0 Example 70.0054 6.51 1205.6 Example 9 0.0017 1.86 1094.1 Example 10 0.0014 3.272335.7 Example 13 0.0012 6.20 5166.7 Example 14 0.003 >10 >3333.3Example 15 0.0048 9.1 1895.8 Example 19 0.060 2.40 40.0 Example 20 0.0151.82 121.3 Example 21 0.0053 >10 >1886.8 Example 22 0.0032 6.56 2050.0Example 23 0.0094 >10 >1063.8 Example 24 0.0015 7.29 4860.0 Example 250.03 17 566.7 Example 27 0.00049 7.16 14612.2 Example 28 0.00065 6.9710723.1 Example 29 0.017 >10 >588.2 Example 30 0.022 >10 >454.5 Example35 0.0075 5.22 696.0 Example 36 0.0041 — — Example 38 0.00093 — —Example 39 0.035 >10 >285.7 Example 40 0.0054 4.2 777.8 control chemical0.13 17.8 136.9

As is apparent from the results shown in Table 1, the compounds of thepresent invention have excellent inhibitory effect for BCR-ABL tyrosinekinase. K562 cells used in Test Example 1 were BCR-ABL positive cells,which had been collected from pleural effusion in a late chronicmyelogenous leukemia patient who had been subjected to acutetransformation. U937 cells were malignant BCR-ABL negative cells thathad been collected from a patient of histiocytic lymphoma. As isapparent from the cell growth inhibitory ratio (U937 cells/K562 cells),the compounds of the present invention are drugs having higher safetythan a control drug.

Furthermore, the compounds of the present invention have cell growthinhibitory effect several hundreds times stronger compared to a controldrug and therefore it can be expected that they exhibit adequate cellgrowth inhibitory effect on not only previously known mutant kinases,but also mutant kinases that would be found in the future. Accordingly,the compounds of the present invention are very useful as a therapeuticagent for diseases such as chronic myelogenous leukemia, acutelymphoblastic leukemia and acute myelogenous leukemia.

TEST EXAMPLE 2

Self-phosphorylation inhibitory effect on mutant (E255K) BCR-ABL

293T cells (purchased from ATCC) were cultured in a Dulbecco's ModifiedEagle Medium (manufactured by Sigma) containing 10% FCS (DMEM/FCS). Thecells were seeded in an amount of 5 ml in a Poly-L-Lysin coated 6 cmdish so as to give 1.2×10⁶ cells/well. The dish was incubated in a CO₂incubator overnight. Using a Lipofectamine reagent (manufactured byInvitrogen), 2 μg of E255K mutant bcr-abl gene expression vector wastransfected into the cell. 16 Hours after the transfection 5 μl of atest drug prepared with DMSO (manufactured by Nacalai tesque) so as togive 1000 times higher concentration was added in each well. The dishwas incubated in a CO₂ incubator for 2 hours. After treatment withtrypsin, the cells were collected into a 15 ml centrifuge tube. The tubewas centrifuged at 1000 rpm at room temperature for one minute. Afterremoval of the medium, 50 μl of a cell lysis solution was added. Thecells were subjected to cytolysis with a mixer. The tube was left tostand at 4° C. for 15 minutes and transferred to 1.5 ml tube. The tubewas centrifuged at 12,000 rpm at 4° C. for 15 minutes. The cell lysatewas collected into another 1.5 ml tube. The concentration of protein wasmeasured according to BCA method. The samples of cell lysate containing5 μl of protein was analyzed by SDS-PAGE polyacrylamide. Afterelectrophoresis, the protein was transferred onto a nylon filter(Hybond-P) with wet method at 4° C. overnight. The nylon filter wasreacted in 10 ml of PBS/0.1% Tween-20 containing 0.2 μg/mlanti-phosphorylation tyrosin kinase antibody (PY99) (manufactured byToyobo) at room temperature for one hour. The nylon filter was washedwith PBS three times and then reacted 10 ml of PBS/0.1% Tween-20containing 0.4 μg/ml Anti-mouse IgG AP-conjugated (manufactured by CellSignaling) at room temperature for one hour. After the nylon filter waswashed with PBS four times, self-phosphorylation of p210 BCR-ABL wasdetected with alkaline phosphatase color developing reagent.

The results are shown as follows: +++: almost perfectly inhibition ofphosphorylation; ++: around half of inhibition; +: week inhibition; and−: no inhibition.

As a control drug,4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide(see Patent document 1) was used. TABLE 2 Self-phosphorylationinhibitory effect on E255K mutant BCR-ABL Test drugs 0.1 μM 0.3 μM 1 μM3 μM 10 μM Example 1 − − + ++ +++ Example 2 + ++ +++ Example 3 − + +++Example 4 − − + Example 5 +++ +++ +++ Example 6 − + +++ +++ +++ Example7 − ++ +++ Example 9 + ++ +++ Example 10 − − ++ +++ +++ Example 13 − +++ +++ +++ Control chemical − − − − −

As is apparent from the results shown in Table 2, the compounds of thepresent invention have self-phosphorylation inhibitory effect on E255Kmutant BCR-ABL tyrosin kinase. Thus, it is possible to inhibit cellgrowth caused by the mutant kinase. Particularly, a control drug had noinhibitory effect and therefore it is apparent that this effect ischaracteristic for the compounds of the present invention.

Furthermore, the compounds of the present invention have also a strongself-phosphorylation inhibitory effect on E255K mutant BCR-ABL tyrosinkinase, on which there is no self-phosphorylation inhibitory effect withsome control drugs and therefore it can be expected that they exhibitadequate self-phosphorylation inhibitory effect on mutant kinases thatwould be found in the future. Accordingly, the compounds of the presentinvention are very useful as a therapeutic agent for diseases such aschronic myelogenous leukemia, acute lymphoblastic leukemia, acutemyelogenous leukemia.

FORMULATION EXAMPLE 1

Tablet (oral tablet)

Formulation/tablet (in 80 mg) Compound of Example 1 5.0 mg Corn Starch46.6 mg Crystalline cellulose 24.0 mg Methyl cellulose 4.0 mg Magnesiumstearate 0.4 mg

The mixed powder of this composition is compressed by a conventionalmethod and molded to make oral tablets.

FORMULATION EXAMPLE 2

Tablet (oral tablet)

Formulation/tablet (in 80 mg) Compound of Example 2 5.0 mg Corn Starch46.6 mg Crystalline cellulose 24.0 mg Methyl cellulose 4.0 mg Magnesiumstearate 0.4 mg

The mixed powder of this composition is compressed by a conventionalmethod and molded to make oral tablets.

INDUSTRIAL APPLICABILITY

As described above, since the compound of the present invention is acompound having excellent BCR-ABL tyrosine kinase inhibitory activity, apharmaceutical composition comprising the compound of the presentinvention as an active ingredient is useful as a BCR-ABL tyrosine kinaseinhibitor, a therapeutic agent for chronic myelogenous leukemia, atherapeutic agent for acute myelogenous leukemia and a therapeutic agentfor acute lymphoblastic leukemia for mammals including humans.

1. An amide derivative, which is a compound represented by the followingformula [1] in any of the following cases (A) and (B), or a saltthereof.

(A) R¹ represents a saturated cyclic amino group (the saturated cyclicamino group may be substituted by 1 to 3 same or different membersselected from the group consisting of alkyl, alkoxycarbonyl, halogen,haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl,monoalkylcarbamoyl and dialkylcarbamoyl), monoalkylamino ordialkylamino. R² represents alkyl, halogen, haloalkyl, hydroxyalkyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, acyl, amino, monoalkylarmino,dialkylamino, nitro, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl orcyano. R³ represents hydrogen, halogen or alkoxy. Het1 represents any ofgroups of the following formulas [2] to [8].

Het2 represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or 1,2-dihydropyridazinyl (the Het2 may be substituted by 1 to 3 same ordifferent members selected from the group consisting of alkyl, halogenand amino). Exception is made for a compound wherein R¹ is (i)pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, all of which maybe substituted by 1 to 3 same or different members selected from thegroup consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl,hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl,monoalkylcarbamoyl and dialkylcarbamoyl, (ii) monoalkylamino, or (iii)dialkylamino, Het1 is a group of the formula [6], and Het2 is pyrazinylor pyridyl which may be substituted by alkyl. (B) R¹ represents4-methylpiperazin-1-yl, 1-pyrrolidinyl, piperidino,4-ethylpiperazin-1-yl, 4-n-propylpiperazin-1-yl,cis-3,5-dimethylpiperazin-1-yl, morpholino, dimethylamino ordiethylamino. R² represents methyl, halogen, trifluoromethyl, methoxy,methoxycarbonyl, nitro, dimethylcarbamoyl or cyano. R³ representshydrogen, bromo or methoxy. Het1 represents a group of the formula [6]Het2 represents 3-pyridyl.
 2. The amide derivative according to claim 1,or a salt thereof, wherein R¹ is a saturated cyclic amino group (thesaturated cyclic amino group may be substituted by 1 to 3 same ordifferent members selected from the group consisting of alkyl andalkoxycarbonyl), monoalkylamino or dialkylamino, R² is alkyl, halogen,haloalkyl, alkoxy, alkoxycarbonyl, nitro, dialkylcarbamoyl or cyano, R³is hydrogen, halogen or alkoxy, Het1 is any of groups of the formulas[2] to [8], and Het2 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or1,2-dihydropyridazinyl (the Het2 may be substituted by 1 to 3 same ordifferent halogen).
 3. The amide derivative according to claim 1, whichis a compound selected from the group consisting of the followingcompounds (1) to (40), or a salt thereof: (1)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide(2)3-iodo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,(3)3-chloro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (4)3-fluoro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (5)4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide,(6)4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide, (7)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(2-pyrazinyl)pyrimidin-2-ylamino]phenyl}benzamide, (8)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(6-chloropyridin-3-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamide, (9)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamide, (10)4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylphenyl}benzamide,(11) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(1,2-dihydropyridazin-4-yl) pyrimidin-2-ylamino]-4-methylphenyl}benzamide,(12)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridazinyl)pyrimidin-2-ylamino]phenyl}benzamide, (13)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide, (14)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyridin-2-ylamino]phenyl}benzamide. (15)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridin-2-ylamino]phenyl}benzamide. (16)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyridin-6-ylamino]phenyl}benzamide, (17)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)pyridin-5-ylamino]phenyl}benzamide, (18)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)phenylamino]phenyl}benzamide, (19)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino]phenyl}benzamide, (20)3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[5-(3-pyridyl)-1,2, 4-triazin-3-ylamino]phenyl}benzamide, (21)3-methyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (22)4-(4-methylpiperazin-1-ylmethyl)-3-nitro-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (23)3-methoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (24)3,5-dibromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (25)3,5-dimethoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (26)3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino)phenyl}benzamide, (27)3-bromo-4-(4-ethylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (28)3-bromo-4-[4-(n-propyl)piperazin-1-ylmethyl]-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (29)3-bromo-4-(N,N-dimethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (30)3-bromo-4-(N,N-diethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (31)3-bromo-4-(1-pyrrolidinylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino)phenyl}benzamide, (32)3-bromo-4-(piperidinomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (33)3-bromo-4-(morpholinomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (34)3-bromo-4-(cis-3,5-dimethylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (35)3-bromo-4-(4-methyl-hexahydro-1H-1,4-diazepin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, (36)3-bromo-4-(1-piperazinylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide, (37)4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide, (38)4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino)phenyl}benzamide, (39)3-methoxycarbonyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide, and (40)3-cyano-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide.
 4. A pharmaceutical compositioncomprising the amide derivative of claim 1 or a salt thereof as anactive ingredient.
 5. A BCR-ABL tyrosine kinase inhibitor comprising theamide derivative of claim 1 or a salt thereof as an active ingredient.6. A therapeutic agent for chronic myelogenous leukemia comprising theamide derivative of claim 1 or a salt thereof as an active ingredient.7. A therapeutic agent for acute lymphoblastic leukemia comprising theamide derivative of claim 1 or a salt thereof as an active ingredient.8. A therapeutic agent for acute myelogenous leukemia comprising theamide derivative of any one of claims 1 to 3 claim 1 or a salt thereofas an active ingredient.
 9. A method of treating a subject havingchronic myelogenous leukemia comprising administering to the subject aneffective amount of the amide derivative of claim 1 or a salt thereof.10. A method of treating a subject having acute lymphoblastic leukemiacomprising administering to the subject an effective amount of the amidederivative of claim 1 or a salt thereof.
 11. A method of treating asubject having acute myelogenous leukemia comprising administering tothe subject an effective amount of the amide derivative of claim 1 or asalt thereof.